WO 2006/091671 PCT/US2006/006283
2
IMIDAZO (1,2-A)PYRIDINE COMPOUNDS AS VEGF-R2 INHIBITORS
BACKGROUND OF THE INVENTION
Unwanted angiogenesis is a hallmark of several diseases, such as retinopathies,
psoriasis, rheumatoid arthritis, age-related macular degeneration (AMD), and cancer
(solid tumors). (Folkman, Nature Med., 1, 27-31 (1995)). Because tumors require a
blood supply to survive, angiogenesis is a critical component contributing to the cancer
disease process (E. Ruoslahti, Nature Rev. Cancer, 2, 83-90 (2002). The development of
new agents for the inhibition of angiogenesis therefore represents a promising approach
for cancer therapy (R. Kerbel and J. Folkman, Nature Rev. Cancer, 2, 727-739 (2002).
Another possible benefit to inhibiting tumor angiogenesis is that this approach may lack
the toxic side effects or drug resistance-inducing properties of conventional
chemotherapy (Judah Folkman, Endogenous Inhibitors of Angiogenesis, The Harvey
Lectures, Series 92, pages 65-82 Wiley-Liss Inc., (1998)).
One of the protein kinases which has been shown to be involved in the angiogenic
process is a member of the growth factor receptor tyrosine kinase family called VEGF-
R2 (vascular endothelial growth factor receptor 2, also known as KDR (kinase insert
domain receptor)). VEGF-R2, which is expressed primarily on endothelial cells, binds
the potent angiogenic growth factor VEGF and mediates the subsequent signal
transduction through activation of its intracellular kinase activity. Thus, it is expected
that direct inhibition of the kinase activity of VEGF-R2 will result in the reduction of
angiogenesis even in the presence of exogenous VEGF (see Strawn et al., Cancer
Research, 56, 3540-3545 (1996)), as has been shown with mutants of VEGF-R2 which
fail to mediate signal transduction. (Millauer et al., Cancer Research, 56, 1615-1620
(1996)). The importance of VEGF-R2 as a target for cancer drug therapy was further
indicated in recent studies (S. Rafii et al., Nature Rev. Cancer, 2, 826-835 (2002) and Y.
Shaked et al., Cancer Cell, 7, 101-111 (2004)) which demonstrated that VEGF-R2 is
expressed on bone marrow-derived circulating endothelial precursor cells that can also
contribute to the angiogenesis and growth of tumors. Furthermore, VEGF-R2 appears to
have no function in the adult beyond that of mediating the angiogenic activity of VEGF.
It has been proposed to treat angiogenesis by the use of compounds inhibiting the

i
WO 2006/091671 PCT/US2006/006283
«?-
kinase activity of VEGF-R2. For example, WIPO International Publication No. WO
97/34876 discloses certain cinnoline derivatives that are inhibitors of VEGF-R2, which
are taught to be useful for the treatment of disease states associated with abnormal
angiogenesis and/or increased vascular permeability including diabetes (hyperglycemia),
psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic
nephropathies, atheroma, arterial restinosis, autoimmune diseases, acute inflammation,
ocular diseases with retinal vessel proliferation, and cancer.
Further, WO 03/092595 provides certain imidazo[l,2-a]pyridinyl compounds that
inhibit, regulate, and/or modulate tyrosine kinase signal transduction.
There is still a need, however, for effective inhibitors of protein kinases.
The present invention provides novel imidazo[l,2-a]pyridinyl compounds that
inhibit VEGF-R2 and are therefore useful in the treatment of VEGF-R2 mediated or
dependent diseases such as the treatment of various forms of cancer.
BRIEF SUMMARY OF THE INVENTION
The present invention provides compounds of Formula I:
A compound of Formula (I):

wherein:
R1: is (a) 2-pyridonyl optionally substituted with-(CH2)1-4NR2R3; or
(b) phenyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,
pyridinyl, N-oxo-pyridinyl, or pyrimidinyl, all of which are optionally substituted with
(CH2)o-4NR2R3, C1-C6 alkyl optionally substituted with amino, pyrrolidinyl, or
morpholinyl, or 1-2 substituents independently selected from the group consisting of C1-
C4 alkoxy, halo, (C1-C6 alkyl)sulfonyl, nitro, -sulfonyl(CH2)0.4NR2R3, and
-carbonyl(CH2)0 - 4NR2R3;

WO 2006/091671 PCT/US2006/006283
4
R2 is hydrogen or C1-C6 alkyl optionally substituted with hydroxy;
R3 is hydrogen or C1-C6 alkyl optionally substituted with hydroxy,
trifluoromethyl, or pyrrolidinyl; or R2, R3, and the nitrogen to which they are attached
form piperidinyl, piperazinyl optionally substituted with C1-C6 alkyl, or morpholinyl;
R4 is thiazolyl, pyridinyl, or phenyl optionally substituted with 1-3 substituents
selected from the group consisting of halo, amino, methyl, trifluoromethyl, and nitro;
R5 is C(O)NHR6, OC(O)NHR6, NHC(O)CH2R6, NHC(O)NHR6 or C(S)NHR6;
n is 0-4 for OC(O)NHR6, NHC(O)CH2R6, NHC(O)NHR6 and n is 1-4 for
C(O)NHR6 and C(S)NHR6; and
R6 is (a) unsubstituted tetrahydrobenzothiazolyl; or
(b) phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, isothiazolyl,
thiadiazolyl, isoxazolyl, all of which are optionally substituted with 1-3 substituents
independently selected from the group consisting of C1-C6 alkyl optionally substituted
with hydroxy, dimethylamino, pyrrolidinyl, piperidinyl, or morpholinyl, C2-C6 alkenyl
optionally substituted with dimethylaminocarbonyl, C1-C6 alkoxy, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, dimethylaminoethoxy, phenoxy, tolyl, halo,
methylsulfonyl, dimethylamino, diethylamino, cyano, C3-C6 cycloalkyl optionally
substituted with hydroxy, methoxy, methoxyethoxy, or methyl, 3,4-dimethylisoxazol-5-
yl-aminosulfonyl, tetrahydiopyranyl, tetrahydropyranylaminocarbonyl, C2-C6
alkylcarbonyl, morpholinylcarbonyl, and piperazinylcarbonyl; or
pharmaceutically acceptable salts thereof.
The present invention further provides a method of inhibiting VEGF-R2 in a
mammal comprising administering to a mammal in need of such treatment a VEGF-R2
inhibiting amount of a compound of Formula I or a pharmaceutically acceptable salt
thereof.
The present invention further provides a method of blocking angiogenesis
comprising administering to a mammal in need of such treatment a VEGF-R2 inhibiting
amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of treating susceptible neoplasms
in a mammal comprising administering to a mammal in need of such treatment a VEGF-

WO 2006/091671 PCT/US2006/006283
5
R2 inhibiting amount of a compound of Formula I or a pharmaceutically acceptable salt
thereof.
The present invention also provides a method of treating a number of disease
states including hyperglycemia, psoriasis rheumatoid arthritis, Kaposi's sarcoma,
haemangioma, acute and chronic nephropathies, atheroma, arterial restinosis,
autoimmune diseases, acute inflammation, and ocular diseases with retinal vessel
proliferation in a mammal comprising administering to a mammal in need of such
treatment a VEGF-R2 inhibiting amount of a compound of Formula I or a
pharmaceutically acceptable salt thereof.
The present invention also provides a pharmaceutical formulation comprising a
compound of Formula I or a pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable excipients.
This invention also provides the use of a compound of Formula I or a
pharmaceutically acceptable salt thereof for the manufacture of a medicament for the
inhibition of VEGF-R2.
The present invention also provides the use of a compound of Formula I or a
pharmaceutically acceptable salt thereof for the manufacture of a medicament to block
angiogenesis.
The present invention also provides the use of a compound of Formula I or a
pharmaceutically acceptable salt thereof for the manufacture of a medicament for the
treatment of susceptible neoplasms.
The present invention also provides the use of a compound of Formula I or a
pharmaceutically acceptable salt thereof for the manufacture of a medicament for the
treatment of a number of disease states selected from the group consisting of
hyperglycemia, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute
and chronic nephropathies, atheroma, arterial restinosis, autoimmune diseases, acute
inflammation, and ocular diseases with retinal vessel proliferation.
DETAILED DESCRIPTION OF THE INVENTION
The general chemical terms used in the formulae above have their usual
meanings. For example, the term "C1-C6 alkyl" includes straight chain and branched

WO 2006/091671 PCT/US2006/006283
6
alkyls and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, isopentyl, and hexyl moieties. The term "C2-C6 alkenyl" includes straight chain
and branched alkylene groups and include ethylenyl, propylenyl, isopropylenyl,
butylenyl, isobutylenyl, sec-butylenyl, tert-butylenyl, pentylenyl, isopentylenyl, and
hexylenyl moieties. The term "C3-C6 cycloalkyl" includes cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl moieties. The term "C1-C6 alkoxy" includes methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy,
isopentoxy, and hexoxy. The term "halo" is taken to mean chloro, bromo, fluoro, or
iodo. The term "(C1-C6 alkyl)sulfonyl" is taken to mean a sulfonyl group substituted
with a C1-C6 alkyl group.
The term "mammal" is taken to mean any of various warm-blooded vertebrate
animals of the class Mammalia, most preferably humans, characterized by a covering of
hair on the skin and, in the female, milk-producing mammary glands for nourishing the
young. "
The term "susceptible neoplasm" is defined to be a neoplasm that depends upon
VEGF-R2 for its survival, growth, or metastasis.
While all of the compounds of Formula I are useful inhibitors of VEGF-R2,
certain classes of compounds are preferred. The following paragraphs describe such
preferred classes.
a) R1 is pyridinyl;
b) Rl is pyridin-2-yl;
c) Rl is pyridin-4-yl;
d) R1 is substituted pyridinyl;
e) R1 is substituted pyridin-2-yl;
f) R1 is substituted pyridin-4-yl;
g) R1 is pyridinyl substituted with 2-morpholinylpropyI;
h) R1 is thienyl;
i) R1 is thien-2-yl;
j) R1 is thien-3-yl;
k) R1 is phenyl;
1) R1 is methylsulfonylphenyl;

WO 2006/091671 PCT/US2006/006283
7
m) R4 is phenyl;
n) R4 is substituted phenyl;
o) R4 is halophenyl;
p) R4 is chlorophenyl;
q) R4 is 2-chlorophenyl;
r) R4 is fluorophenyl;
s) R4 is 2-fluorophenyl;
t) n is 0;
u) n is 1;
v) R5 is NHC(O)NHR6;
w) R5 is C(O)NHR6;
x) R6 is substituted pyrazolyl;
y) R6 is pyrazolyl substituted with C1-C6 alkyl;
z) R6 is 5-tert-butyl-pyrazol-3-yl;
aa) R6 is substituted phenyl;
bb)R6 is trifluoromethylphenyl;
cc) R6 is m-trifluoromethylphenyl;
dd) R6 is substituted thiadiazolyl;
ee) R6 is thiadiazolyl substituted with C1-C6 alkyl;
ff) R6 is 5-tert-butyl-thiadiazol-2-yl;
gg) R6 is substituted isoxazolyl;
hh)R6 is isoxazolyl substitued with C1-C6 alkyl;
ii) R6 is 5-tert-butyl-isoxazol-3-yl;
jj) R6 is 3-tert-butyl-isoxazol-5-yl;
kk)R6 is substituted thiazolyl;
11) R6 is thiazolyl substituted 1-2 times with C1-C6 alkyl;
mm) R6 i s 5 -tert-butyl -thi azol-2-yl;
nn) R6 is 5-tert-butyl-4-morpholin-4-ylmethyl-thiazol-2-yl;
oo)R6 is 4-methyl-5-i-propylthiazol-2-yl;
pp) R6 is 4-dimethylaminomethyl-5-(l-methylcyclopropyl)thiazol-2-yl;
qq)R6 is substituted pyridinyl;

WO 2006/091671 PCT/US2006/006283
8
rr) R6 is 4-tert-butyl-6-morpholinymethylpyridin-2-yl;
ss) R6 is 4-trifluoromethylpyridin-2-yl;
tt) R1 is pyridinyl, R4 is phenyl, n is 1, R5 is CONHR6, and R6 is 3-
trifluoromethylphenyl;
uu)R1 is pyridinyl, R4 is fluorophenyl, n is 1, R5 is CONHR6, and R6 is 5-tert-
butyl-thiadiazol-2-yl;
vv) R1 is pyridinyl, R4 is fluorophenyl, n is 1, R5 is CONHR6, and R6 is 4-methyl-
5-isopropyl-thiazol-2-yl;
ww) R1 is pyridinyl, R4 is fluorophenyl, n is 1, R5 is CONHR6, and R6 is 4-tert-
butyl-6-morpholinylmethylpyridin-2-yl;
xx)R1 is 2-(2-morpholinylpropyl)pyridin-4-yl, R4 is fluorophenyl, n is 1, R5 is
CONHR6 , and R6 is 4-trifluoromethylpyridinyl; both enantiomers and
racemate;
yy) R1 is pyridinyl, R4 is fluorophenyl, n is 1, R5 is CONHR6, and R6 is 4-
dimethylarnino-5-methylcyclopropylthiazol-2-yl;
zz) R1 is pyridinyl, R4 is fluorophenyl, n is 1, R5 is CONHR6, and R6 is 4-
morpholinylmethyl-5-t-butyl-thiazol-2-yl;
aaa) A compound of Formula I which is 2-[4-(7-pyridin-4-yl-imidazo[l,2-
a ]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-acetamide;
bbb) A compound of Formula I which is N-(5-tert-butyl-[l,3,4]thiadiazol-2-yl)-
2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide;
ccc) A compound of Formula I which is 2-[2-fluoro-4-(7-pyridin-4-yl-
imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(5-isopropyl-4-methyl-thiazol-2-yl)-
acetamide;
ddd) A compound of Formula I which is N-(4-tert-butyl-6-morpholin-4-
ylmethyl-pyridin-2-yl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-
yl)-phenyl]-acetamide;
eee) A compound of Formula I which is 2-(2-fluoro-4-{7-[2-(2-morpholin-4-
yl-propyl)-pyridin-4-yl]-imidazo[l,2-a]pyridin-3-yl}-phenyl)-N-(4-
trifluoromethyl-pyridin-2-yl)-acetamide;

WO 2006/091671 PCT/US2006/006283
9
fff) A compound of Formula I which is N-[4-dimethylaminomethyl-5-(l-methyl-
cyclopropyI)-thiazol-2-yl]-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[ 1,2-
a]pyridin-3-yl)-phenyl]-acetamide;
ggg) A compound of Formula I which is 2-[2-fluoro-4-(7-pyridin-4-yl-
imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[5-tert-butyl-4-morpholin-4-ylmethyl-
thiazol-2-yl]-acetamide;
hhh) A compound of Claim 1 wherein R1s phenyl, thienyl, thiazolyl, or
pyridinyl all of which are optionally substituted with -(CH2)0-4 NR2R3 , C1-C6
alkyl optionally substituted with amino, pyrrolidinyl, or morpholinyl, or 1-2
substituents independently selected from the group consisting of C1-C4
alkoxy, halo, (C1-C6 alkyl)sulfonyl, nitro, -sulfonyl(CH2)0-4 NR2R3, and -
carbonyl(CH2)0-4 NR2R3;
iii) A compound of Claim 1 wherein R1 is 4-pyridinyl which is optionally
substituted with -(CH2)0-4NR2R3, C1-C6 alkyl optionally substituted with
amino, pyrrolidinyl, or morpholinyl, or 1-2 substituents independently
selected from the group consisting of C1-C4 alkoxy, halo, (C1-C6
alkyl)sulfonyl, nitro, -sulfonyl(CH2)0-4 NR2R3, and -carbonyl(CH2)0-4 NR2R3;
and R6 is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, isothiazolyl,
thiadiazolyl, isoxazolyl, all of which are optionally substituted with 1-3
substituents independently selected from the group consisting of C1-C6 alkyl
optionally substituted with hydroxy, dimethylamino, pyrrolidinyl,
piperidinyl, or morpholinyl, C2-C6 alkenyl optionally substituted with
dimethylaminocarbonyl, C1-C6 alkoxy, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, dimethylaminoethoxy, phenoxy, tolyl, halo,
methylsulfonyl, dimethylamino, diethylamino, cyano, C3-C6 cycloalkyl
optionally substituted with hydroxy, methoxy, methoxyethoxy, or methyl,
3,4-dimethylisoxazol-5-yl-aminosulfonyl, tetrahydropyranyl,
tetrahydropyranylaminocarbonyl, C2-C6 alkylcarbonyl, morpholinylcarbonyl,
and piperazinylcarbonyl;
jjj) A compound of Claim 1 wherein R1 is 2-pyridinyl which is optionally
substituted with -(CH2)0-4 NR2R3, C1-C6 alkyl optionally substituted with

WO 2006/091671 PCT/US2006/006283
10
amino, pyrrolidinyl, or morpholinyl, or 1-2 substituents independently
selected from the group consisting of C1-C4 alkoxy, halo, (C1-C6
alkyl)sulfonyl, nitro, -sulfonyl(CH2)0-4 NR2R3, and
-carbonyl(CH2)o-4 NR2 R3; and R6 is phenyl, pyridinyl, thiazolyl,
isothiazolyl, thiadiazolyl, or isoxazolyl, all of which are optionally
substituted with 1-3 substituents independently selected from the group
consisting of C1-C6 alkyl optionally substituted with hydroxy,
dimethylamino, pyrrolidinyl, piperidinyl, or morpholinyl, C2-C6 alkenyl
optionally substituted with dimethylaminocarbonyl, C1-C6 alkoxy,
trifluoromethyl, difluoromethoxy, trifluoromethoxy,
dimethylaminoethoxy, phenoxy, tolyl, halo, methylsulfonyl,
dimethylamino, diethylamino, cyano, C3-C6 cycloalkyl optionally
substituted with hydroxy, methoxy, methoxyethoxy, or methyl, 3,4-
dimethylisoxazol-5-yl-aminosulfonyl, tetrahydropyranyl,
tetrahydropyranylaminocarbonyl, C2-C6 alkylcarbonyl,
morpholinylcarbonyl, and piperazinylcarbonyl.
kkk) A compound of Claim 1 wherein R1 is phenyl which is optionally
substituted with -(CH2)o-4 NR2R3, C1-C6 alkyl optionally substituted with
amino, pyrrolidinyl, or morpholinyl, or 1-2 substituents independently
selected from the group consisting of C1-C4 alkoxy, halo, (C1-C6
alkyl)sulfonyl, nitro, -sulfonyl(CH2)0-4 NR2R3, and -carbonyl(CH2)o-
4NR2R3; and R6 is phenyl, pyridinyl, pyrazolyl, thiazolyl, isothiazolyl,
thiadiazolyl, or isoxazolyl, all of which are optionally substituted with 1-3
substituents independently selected from the group consisting of C1-C6
alkyl optionally substituted with hydroxy, dimethylamino, pyrrolidinyl,
piperidinyl, or morpholinyl, C2-C6 alkenyl optionally substituted with
dimethylaminocarbonyl, C1-C6 alkoxy, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, dimethylaminoethoxy, phenoxy, tolyl, halo,
methylsulfonyl, dimethylamino, diethylamino, cyano, C3-C6 cycloalkyl
optionally substituted with hydroxy, methoxy, methoxyethoxy, or methyl,
3,4-dimethylisoxazol-5-yl-aminosulfonyl, tetrahydropyranyl,

WO 2006/091671 PCT/US2006/006283
11
tetrahydropyranylaminocarbonyl, C2-C6 alkylcarbonyl,
morpholinylcarbonyl, and piperazinylcarbonyl;
HI) A compound of Claim 1 wherein R1 is thienyl or thiazolyl which is
optionally substituted with -(CH2)0-4 NR2R3, C1-C6 alkyl optionally
substituted with amino, pyrrolidinyl, or morpholinyl, or 1-2 substituents
independently selected from the group consisting of C1-C4 alkoxy, halo,
(C1-C6 alkyl)sulfonyl, nitro, -sulfonyl(CH2)o-4NR2R3, and -
carbonyl(CH2)o-4NR2R3; and R6 is phenyl, pyrazolyl, thiazolyl,
isothiazolyl, thiadiazolyl, or isoxazolyl, all of which are optionally
substituted with 1-3 substituents independently selected from the group
consisting of C1-C6 alkyl optionally substituted with hydroxy,
dimethylamino, pyrrolidinyl, piperidinyl, or morpholinyl, C2-C6 alkenyl
optionally substituted with dimethylaminocarbonyl, C1-C6 alkoxy,
trifluoromethyl, difluoromethoxy, trifluoromethoxy,
dimethylaminoethoxy, phenoxy, tolyl, halo, methylsulfonyl,
dimethylamino, diethylamino, cyano, C3-C6 cycloalkyl optionally
substituted with hydroxy, methoxy, methoxyethoxy, or methyl, 3,4-
dimethylisoxazol-5-yl-aminosulfonyl, tetrahydropyranyl,
tetrahydropyranylaminocarbonyl, C2-C6 alkylcarbonyl,
morpholinylcarbonyl, and piperazinylcarbonyl;
mmm) A compound of Claim 1 wherein R1 is 3-pyridinyl which is optionally
substituted with-(CH2)o-4NR2R3, C1-C6 alkyl optionally substituted with
amino, pyrrolidinyl, or morpholinyl, or 1-2 substituents independently
selected from the group consisting of C1-C4 alkoxy, halo, (C1-C6
alkyl)sulfonyl, nitro, -sulfonyl(CH2)0-4NR2R3, and -carbonyl(CH2)o-
4NR2R3; and R6 is phenyl, thiazolyl, isothiazolyl, thiadiazolyl, or
isoxazolyl, all of which are optionally substituted with 1-3 substituents
independently selected from the group consisting of C1-C6 alkyl optionally
substituted with hydroxy, dimethylamino, pyrrolidinyl, piperidinyl, or
morpholinyl, C2-C6 alkenyl optionally substituted with
dimethylaminocarbonyl, C1-C6 alkoxy, trifluoromethyl, difluoromethoxy,

WO 2006/091671 PCT/US2006/006283
12
trifluoromethoxy, dimethylaminoethqxy, phenoxy, tolyl, halo,
methylsulfonyl, dimethylamino, diethylamino, cyano, C3-C6 cycloalkyl
optionally substituted with hydroxy, methoxy, methoxyethoxy, or methyl,
3,4-dimethylisoxazol-5-yl-aminosulfonyl, tetrahydropyranyl,
tetrahydropyranylaminocarbonyl, C2-C6 alkylcarbonyl,
morpholinylcarbonyl, and piperazinylcarbonyl;
nnn) A compound of Formula 1 which is selected from the group consisting of
HC1, diHCL, succinate, L-tartrate, and HBr salts;
000) A compound of Formula I which is selected from the group consisting of
HC l and HBr salts; and
ppp) A compound of Formula I which is a succinate salt.
It will be understood that the above classes may be combined to form additional
preferred classes.
Another preferred class of the present invention is compounds of Formula II:

wherein:
R1: is (a) 2-pyridonyl optionally substituted with-(CH2)1-4NR2R3; or
(b) phenyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,
pyridinyl, N-oxo-pyridinyl, or pyrimidinyl, all of which are optionally substituted with -
(CH2)0-4 NR2R3, C1-C6 alkyl optionally substituted with amino, pyrrolidinyl, or
morpholinyl, or 1-2 substituents independently selected from the group consisting of C1-
C4 alkoxy, halo, (C1-C6 alkyl)sulfonyl, nitro, -sulfonyl(CH2)0-4 NR2R3, and
-carbonyl(CH2)o-4 NR2R3;
R2 is hydrogen or C1-C6 alkyl optionally substituted with hydroxy;

WO 2006/091671 PCT/US2006/006283

13
R3 is hydrogen or C1-C6 alkyl optionally substituted with hydroxy,
trifluoromethyl, or pyrrolidinyl; or R2, R3, and the nitrogen to which they are attached
form piperidinyl, piperazinyl optionally substituted with C1-C6 alkyl, or morpholinyl;
R4 is thiazolyl, pyridinyl, or phenyl optionally substituted with 1-3 substituents
selected from the group consisting of halo, ammo, methyl, trifluoromethyl, and nitro; and
R6 is (a) unsubstituted tetrahydrobenzothiazolyl; or
(b) phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, isothiazolyl,
thiadiazolyl, isoxazolyl, all of which are optionally substituted with 1-3 substituents
independently selected from the group consisting of C1-C6 alkyl optionally substituted
with hydroxy, dimethylamino, pyrrolidinyl, piperidinyl, or morpholinyl, C2-C6 alkenyl
optionally substituted with dimethylaminocarbonyl, C1-C6 alkoxy, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, dimethylaminoethoxy, phenoxy, toiyl, halo,
methylsulfonyl, dimethylamino, diethylamino, cyano, C3-C6 cycloalky] optionally
substituted with hydroxy, methoxy, methoxyethoxy, or methyl, 3,4-dimethylisoxazol-5-
yl-aminosulfonyl, tetrahydropyranyl, tetrahydropyranylaminocarbonyl, C2-C6
alkylcafbonyl, morpholinylcarbonyl, and piperazinylcarbonyl; or
pharmaceutically acceptable salts thereof.
Another preferred class of the present invention is compounds of Formula III:

wherein:
R1: is (a) 2-pyridonyl optionally substituted with-(CH2)1-4 NR2R3; or
(b) phenyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,
pyridinyl, N-oxo-pyridinyl, or pyrimidinyl, all of which are optionally substituted with -
(CH2)o-4 NR2R3, C1-C6 alkyl optionally substituted with amino, pyrrolidinyl, or
morpholinyl, or 1-2 substituents independently selected from the group consisting of C1-
C4 alkoxy, halo, (C1-C6 alkyl)sulfonyl, nitro, -sulfonyl(CH2)o-4 NR2R3, and

WO 2006/091671 PCT/US2006/006283
14
-carbonyl(CH2)outNR2R3;
R2 is hydrogen or C1-C6 alkyl optionally substituted with hydroxy;
R3 is hydrogen or C1-C6 alkyl optionally substituted with hydroxy,
trifluoromethyl, or pyrrolidinyl; or R2, R3, and the nitrogen to which they are attached
form piperidinyl, piperazinyl optionally substituted with C1-C6 alkyl, or morpholinyl;
R4 is thiazolyl, pyridinyl, or phenyl optionally substituted with 1-3 substituents
selected from the group consisting of halo, amino, methyl, trifluoromethyl, and nitro; and
R6 is (a) unsubstituted tetrahydrobenzothiazolyl; or
(b) phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, isothiazolyl,
thiadiazolyl, isoxazolyl, all of which are optionally substituted with 1-3 substituents
independently selected from the group consisting of C1-C6 alkyl optionally substituted
with hydroxy, dimethylamino, pyrrolidinyl, piperidinyl, or morpholinyl, C2-C6 alkenyl
optionally substituted with dimethylaminocarbonyl, C1-C6 alkoxy, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, dimethylaminoethoxy, phenoxy, tolyl, halo,
methylsulfonyl, dimethylamino, diethylamino, cyano, C3-C6 cycloalkyl optionally
substituted with hydroxy, methoxy, methoxyethoxy, or methyl, 3,4-dimethylisoxazol-5-
yl-aminosulfonyl, tetrahydropyranyl, tetrahydropyranylaminocarbonyl, C2-C6
alkylcarbonyl, morpholinylcarbonyl, andpiperazinylcarbonyl; or
pharmaceutically acceptable salts thereof.
Another embodiment of the present invention is a compound of Formula (IV):

wherein:
R1: is (a) 2-pyridonyl optionally substituted with C1-C6 alkyl or -(CH2)1-4NR2R3;
or

WO 2006/091671 PCT/US2006/006283
15
(b) phenyl, thienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl,
tetrazolyl, oxazolyl, isoxazolyl, pyridinyl, or pyrimidinyl, all of which may be optionally
substituted with -(CH2)0-4NR2R3 or 1-2 substituents independently selected from the
group consisting of C1-C6 alkyl, C1-C4 alkoxy, halo, and (C1-C6 alkyl)sulfonyl,
-sulfonyl(CH2)o-4NR2R3, or -carbonyl(CH2)0-4NR2R3;
R2 is hydrogen or C1-C6 alkyl;
R3 is hydrogen, C1-C6 alkyl optionally substituted with pyrrolidinyl, piperidinyl,
piperazinyl optionally substituted with C1-C4 alkyl, or morpholinyl; or R2 and R3 taken
together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl,
piperazinyl optionally substituted with C1-C4 alkyl, or morpholinyl;
R4 is thiazolyl, thienyl, pyridinyl, or phenyl optionally substituted 1-2 times with
halo;
n is 0-4;
R5 is C(O)NHR6, OC(O)NHR6, NHC(O)CH2R6, or NHC(O)NHR6;
R6 is phenyl optionally substituted with 1-3 substituents independently selected
from the group consisting of halo, C1-C6 alkyl, C1-C4 alkoxy, cyano, dimethylamino,
difluoromethoxy, trifluoromethyl, trifluoromethoxy, methylsulfonyl,
dimethylisoxazolylsulfonamide, and -O-phenyl, pyridinyl optionally substituted with
trifluoromethyl, pyrazolyl optionally substituted with 1-2 substituents independently
selected from the group consisting of tolyl and C1-C6 alkyl that is optionally substituted
with hydroxy, piperidinyl, pyrrolidinyl, or morpholinyl, (C2-C6 alkyl)isoxazolyl, (C1-C6
alkyl)thiazolyl, (C1-C6 alkyl)isothiazolyl, (C1-C6 alkyl)thiadiazolyl;
R7 is H, or C1-C6 alkyl; or
pharmaceutically acceptable salts thereof.
The compounds of the present invention are inhibitors of VEGF-R2, a protein
kinase which has been shown to be involved in the angiogenic process. VEGF-R2, which
is expressed primarily on endothelial cells, binds the potent angiogenic growth factor
VEGF and mediates the subsequent signal transduction through activation of its
intracellular kinase activity. Thus, one skilled in the art would recognize that direct
inhibition of the kinase activity of VEGF-R2 will result in the reduction of angiogenesis
and thus affect treatment of conditions wherein abnormal angiogenesis and/or increased

WO 2006/091671 PCT/US2006/006283
16
vascular permeability is a hallmark, for example, diabetes(hyperglycemia), psoriasis,
rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies,
atheroma, arterial restinosis, autoimmune diseases, acute inflammation, ocular diseases
with retinal vessel proliferation, and cancer. The utility of angiogenesis inhibitors in the
treatment of cancer is known in the literature, see J. Rak et al. Cancer Research, 55:4575-
4580,1995 for example. The role of angiogenesis in cancer has been shown in numerous
types of cancer and tissues: Breast carcinoma (G. Gasparinin and A.L. Harris, J. Clin.
Oncol, 1995,13:765-782; M. Toi et al. Japan. J. Cancer Res., 1994, 85:1045-1049);
bladder carcinomas (A.J. Dickinson et al., Br. J. Uroi, 1994, 74:762-766) colon
carcinomas (L.M. Ellis et al., Surgery, 1996, 120(5): 871-878); and oral cavity tumors
(J.K. Williams et al., Am J. Surg., 1994, 168:373-380). Preferred neoplasms believed to
be susceptible to treatment by compounds of the present invention include the following
cancers: brain, genitourinary tract, lymphatic system, stomach, larynx, lung (including
small cell and non-small cell), pancreas, breast, prostate, histiocytic, lymphoma,
hepatocelllular, gynecologic (e.g. ovarian), Kaposi's sarcoma, CNS tumors (including
astrocytomas, medulloblastomas, and meningiomas), colorectal, head and neck cancer,
melanoma, chronic lymphocytic leukemia, multiple myeloma, acute myeloid leukemia
(AML), chronic myelogenous leukemia (CML), malignant mesothelioma,
myelodysplastic syndrome" (e.g., polycythemia vera, thrombocytemia), gastric cancer,
and renal cell carcinoma.
The skilled artisan will appreciate that the introduction of certain substituents will
create asymmetry in the compounds of Formula I. The present invention contemplates all
enantiomers and mixtures of enantiomers and stereoisomers, that is, both the
stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or
diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric
and stereoisomeric mixtures can be resolved into their component enantiomers or
stereoisomers by well known methods, such as, chiral-phase high performance liquid
chromatography or crystallizing the compound as a chiral salt complex. Enantiomers and
stereoisomers can also be obtained from stereomerically- or enantiomerically-pure
intermediates, reagents, and catalysts by well known asymmetric synthetic methods.

WO 2006/091671 PCT/US2006/006283
17
Pharmaceutically acceptable salts are contemplated to be within the scope of the
present invention. The compounds of the present invention are bases and salts of such
compounds may be formed with inorganic or organic acids, for example, HC1, diHCl,
succinate, L-tartrate, and HBr with HC1, diHCl and succinate being preferred.
The compounds of this invention may be prepared by employing reactions as
shown in the following schemes, in addition to other standard manipulations that are"
known in the literature or exemplified in the experimental procedures. These schemes,
therefore, are not limited by the compounds listed or by any particular substituents
employed for illustrative purposes.
The following schemes are used to prepare compounds of Formula I where R5 is
NHC(O)CH2R6 or NHC(O)NHR6. Unless otherwise indicated, all other variables are as
previously defined.
Scheme I

The urea (AE) compounds of Formula I may be generally prepared by reaction of
an amine (AA) with a carbamate (AB), a carbamoyl chloride (AC), or an aryl isocyanate
(AD), all of which are commercially available or directly prepared by methods known to

WO 2006/091671 PCT/US2006/006283
18
those skilled in the art. The amide (AG) compounds of Formula I may be generally
prepared by reaction of an amine (AA) with an acyl chloride (AF).
The requisite amine (AA) intermediate may be prepared from known 7-chloro-
imidazo[l,2-a]pyridine (AH) as in Scheme II. X is Cl, Br, or I, and Y is a boronic acid,
boronic ester, or trialkyl stannane. Unless otherwise indicated, all other variables are as
previously defined.

An aryl group is introduced at the 7-position of the imidazo[l,2-a]pyridine group
by Pd catalyzed cross-coupling or through the intermediacy of a boronic ester to give the
biaryl compound (AI). This intermediate (AI) is halogenated selectively with NIS or
NBS at the 3-position followed by a second cross-coupling reaction at that position. An
amino or aminoalkyl group or a latent amino or aminoalkyl group is a substituent of the
aryl boronate coupling partner. Alternatively, the couplings may be carried out first at
the 3-position and then at the 7-position through the intermediacy of (AK) and (AL) as
depicted in Scheme II. It should also be noted that the cross-coupling reaction used to

WO 2006/091671 PCT/US2006/006283
19
install the aryl group at the 7-position of the imidazo[l,2-a]pyridine can take place at the
end of the sequence, after formation of the urea (not pictured).
The amides of Formula 1 may be prepared as shown in Scheme III. Unless
otherwise indicated, all variables are as previously defined.

Alternatively
bis(pinacolato)diboron,
CDI R3 N
X-R4-(CH2)n-CO2H +H2N-R6 —~ X-R4-(CH2)n-CONHR6 -
(AP) KOAc,Pd(0),P(c-hex)3
(AO)
Fd(0),K2Co3.
Y-R4-(CH2)n-CONHR6 + (AJ)or(AK) (AN)
(AQ) dioxaneH2O
A Pd(0) catalyzed cross-coupling of (AJ) or (AK) with a phenyl boronic acid that
is appended with an alkyl tethered carboxylic acid (or protected acid) provides (AM).
The carboxylate group is coupled to an amine using standard methods well-known to
those skilled in the art resulting in (AN). Alternatively, the amide (AP) can be prepared
from a halophenyl acid (AO) using standard methods before the aryl group is coupled to

WO 2006/091671 PCT/US2006/006283
20
the imidazo[l,2-a]pyridine ring. In this case a halide substituent on the aryl group (AP)
is converted to a boronic ester (AQ) for coupling to (AJ) or (AK) as shown in Scheme III.
In the cases where a halogen occupies the 7-position of the imidazo[l,2-a]pyridine ring in
(AN), a second Pd(0) catalyzed coupling is carried out to obtain the claimed compound
as previously described in Scheme I.
The carbamates of Formula I may be prepared as shown in Scheme IV. Unless
otherwise indicated, all variables are as previously defined.

The carbamates (AR) are formed by combining an alcohol (AM ') with an
isocyanate. Synthesis of this starting material (AM ') is by Pd(0) catalyzed cross-
coupling at the 3-position of the imidazo[l,2-a]pyridine (AK or AJ) with an alcohol such
as hydroxylmethylphenylboronic acid. The aryl group at the 7-position of the
imidazo[l,2-a]pyridine can be introduced by a second Pd(0) coupling at any point as
shown for the ureas.
Compounds of Formula I where R1 is pyridonyl, methoxy substituted pyridinyl, or
di(substituted)aminopyridinyl may be prepared as shown is Scheme V. Unless
otherwised indicated, all other variables are as previously defined.

WO 2006/091671 PCT/US2006/006283

21

A dialkylaraino group can be introduced by nucleophilic aromatic substitution of
a 2-fluoropyridyl group (AS) to yield (AT) at the end of the synthesis. A similar strategy
using acidic methanolysis gives (AU), and methyl ether cleavage with HBr provides the
pyridonyl group (AV).
The aryl bromides of Scheme II, R1X, may be prepared as described in Scheme
VI. R7 is as previously described.

An alkyl- or dialkylaminomethyl pyridyl group can be introduced as a substituent
on the aryl group at the 7-position of the imidazo[l,2-a]pyridine via alkylation of 5-
bromo-2-bromomethyl-pyridine (AW) with a secondary amine, as shown in Scheme VI.
The aryl bromide (s) can then participate directly is the reactions previously described.

WO 2006/091671 PCT/US2006/006283
22

Compounds from the amide class may also be prepared as shown in Scheme VII
via the Pd(0) catalyzed arylation reaction of 3-H imidazo[l,2,a]pyridine intermediates
(AH) or (AT) with a protected (PG) bromophenyl acetic acid ester (AX) to form the
coupled acid (AY). The tert-butyl group is a suitable ester protecting group indicated as
PG which is subsequently cleaved under acidic conditions. The amide (AN) may then be
formed using either oxalyl chloride/DMF to form an acyl chloride in situ or using the
coupling reagents DMTMM/NMM or HATU/diisopropylethyl amine.

Alternately, The amides (BA) are prepared from bromoarylacids (AZ) using the
amide formation procedures above, and the BA are coupled via the Pd(0) catalyzed
arylation reaction with (AH) or (AI). In the cases where the Pd(0) catalyzed arylation
reaction is carried out with (AH), subsequent elaboration is carried out at the Cl
substituted position as previously described.
The skilled artisan will appreciate that not all of the substituents in the compounds
of Formula I will tolerate certain reaction conditions employed to synthesize the

WO 2006/091671 PCT/US2006/006283
23
compounds. These moieties may be introduced at a convenient point in the synthesis, or
may be protected and then deprotected as necessary or desired. The skilled artisan will
appreciate that the protecting groups may be removed at any convenient point in the
synthesis of the compounds of the present invention. Methods for introducing and
removing nitrogen and oxygen protecting groups are well known in the art; see, for
example, Greene and Wuts, Protective Groups in Organic Synthesis. 3rd Ed., John Wiley
and Sons, New York, Chapter 7 (1999). Furthermore, the skilled artisan will appreciate
that in many circumstances, the order in which moieties are introduced is not critical.
The particular order of steps required to produce the compounds of Formula I can be
dependent upon the particular compound being synthesized, the starting compound, and
the relative lability of the substituted moieties.
Abbreviations
AIBN - 2,2'-Azobis(2-methyl propionitrile); BINAP - rac-2,2'-Bis(diphenyl-phosphino)-
l.l'-binaphthyl; 9-BBN - 9-Borabicyclo[3.3.1]nonane; Boc2O -Di-tert-butyl
dicarbonate; TBDMSC1 or TBDMSiCl - tert-butyl-dimethylsilyl chloride; TBAF - tert-
Butylamine hydrofluoride; MS (ES) - Electrospray Mass spectrum; THF -
tetrahydrofuran; DMEA - Dimethylethylamine; DMSO - Dimethylsulfoxide; DMF -
Dimethylformamide; DME - Dimethyl ethylene glycol; DCM - dichloromethane;
Dioxane - 1,4-dioxane; DMAP - 4-Dirnethylaminopyridine; h - hour(s); LDA -
Lawesson Reagent- 2,4-Bis-(4-methoxy phenyl)-l,3-dithia-2,4-diphosphetone-2,4-
disulfide; lithium di-isopropylamine; NIS - N-iodosuccinimide; min - minute(s); NBS -
N-romosuccinimide; MeOH - methanol; EtOH - 95% ethanol; RBF, RB - round bottom
flask; RBSN - round bottom single neck flask; SiO2 - silica gel; EtOAc, AcOEt -
ethylacetate; ESIMS - electrospray ionization mass spectrometry; HPLC - high pressure
liquid chromatography; ISCO - ISCO brand high pressure liquid chromatography; S-
Phos - 2-Dicyclohexyl-phosphino-2',6'-dimethoxy-l,l'-biphenyl; Pd(TPP)4 -
tetrakis(triphenylphosphine)-palladium(0);DMTMM - 4-(4,6-dimethoxy-[l ,3,5]triazin-2-
yl)-4-methyl-morpholin-4-ium; chloride; NMM - N-Methylmorpholine; HATU - O-(7-
Azabenzotriazole-l-yl)-N, N,N'N'-tetramethyluronium hexafluorophosphate; NMP -1-
Methyl-2-pyrrolidinone; PdCl2(dppf) CH2C12- l,r-Bis-(diphenylphosphino)ferrocene

WO 2006/091671 PCT/US2006/006283
24

palladium(II) dichloride Dichloromethane complex; X-Phos - 2-Dicyclohexylphosphino-
2',4',6'-tri-i-propyl-l,r-biphenyl. NMP- l-Methyl-2-pyrrolidinone; Pearlman's catalyst
-Palladium hydroxide, 20 wt% Pd on carbon;
Preparation 1
5-tert-Butyl-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyI]-2H-pyrazol-3-ylamine
A. 2-(5-Amino-3-tert-butyl-pyrazol-l-yl)-ethanol
To a solution of 4,4-dimethyl-3-oxo-pentanenitrile (5.0 g, 0.04 mol) in absolute
ethanol (50 mL), add 2-hydrazino-ethanol (3 mL, 1.1 equiv.) and concentrated HC1 (0.5
mL). Reflux the reaction for 4 hours then cool to room temperature and dilute with water
and ethyl acetate. Wash the organics with water then saturated aqueous saturated sodium
chloride then dry with magnesium sulfate, filter and concentrate in vacuo. Trituration
from hexanes and dichloromethane gives a white solid (4.8 g, 66%). MS (ES), m/z 184
(M+l).
B. 5-tert-Butyl-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2H-pyrazol-3-ylamine
To 2-(5-amino-3-tert-butyl-pyrazol-l-yl)-ethanol (3.42 g, 0.019 mol), add
TBDMSC1 (3.38 g, 1.2 equiv.) and imidazole (3.18 g, 2.5 equiv.) in DMF (7 mL) and stir
overnight at room temperature under N2. Dilute the reaction with ethyl acetate and water.
Wash the organic layer with water then saturated aqueous saturated sodium chloride and
then dry over magnesium sulfate, filter, and concentrate in vacuo to give a solid (5.5 g,
99%) which is used without further purification. MS (ES), m/z 298 (M+l).
Make the following intermediates according to the general procedure described in
the PCT application WO200026202 May 11, 2000, filed Oct 27, 1999 (p.52):

Preparation Name Physical Data MS(ES), m/z (M+l)
2 5-Ethyl-thiazol-2-ylamine 129
3 5-Propyl-thiazol-2-ylamine 143
4 5 -Isopropyl-thiazol-2-ylamine 143
5 5-tert-Butyl-thiazol-2-ylamine 157

WO 2006/091671 PCT/US2006/006283
25
Preparation 6
2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-(5-tert-butyl-2H-pyrazol-3-yl)-carbamic acid
2,2,2-trichloro-ethyl ester
Dissolve 5-tert-butyl-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2H-pyrazol-3-ylamine
(5.5 g, 0.018 mol) in THF (100 mL) under N2 and cool to 0 °C. Add pyridine (1.6 mL,
1.1 equiv.) via syringe followed by dropwise addition of 2,2,2-trichloroethyl
chloroformate (2.7 mL, 1.1 equiv.). Stir the reaction at 0 °C for one hour then remove
the cooling bath and allow the reaction to stir for a total of 5 hours. Dilute the reaction
with ethyl acetate and water. Wash the organic layer with water then saturated aqueous
saturated sodium chloride and then dry over magnesium sulfate, filter, and concentrate in
vacuo to give a residue (8.7 g, 100%) that is used without further purification. MS (ES),
m/z 474 (M+l).
Using a procedure similar to Preparation 6, prepare the following intermediates
from commercially available starting materials or those described in Preparations 1-5:

Prep. Name Physical DataMS(ES), m/z(M+l)
7 (3-tert-Butyl-isoxazol-5-yl)-carbamic acid 2,2,2-trichloro-ethylester 317
8 [3-(l-Ethyl-l-methyl-propyl)-isoxazol-5-yl]-carbamic acid 2,2,2-trichloro-ethyl ester 345
9 [3-(l,l-Dimethyl-butyl)-isoxazol-5-yl]-carbamic acid 2,2,2-trichloro-ethyl ester 345
10 (5-tert-Butyl-isoxazol-3-yl)-carbamic acid 2,2,2-trichloro-ethylester 317
11 (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester 406
12 3-tert-Butyl-5-(2,2,2-trichloro-ethoxycarbonylamino)-pyrazole-l-carboxylic acid tert-butyl ester 415
13 (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester 328
14 (5-tert-Butyl-[l,3,4]thiadiazol-2-yl)-carbamic acid 2,2,2-trichloro-ethyl ester 332
15 (5-Ethyl-thiazol-2-yl)-carbamic acid 2,2,2-trichloro-ethyl ester 304

WO 2006/091671 PCT/US2006/006283
26

16 (5-Propyl-thiazol-2-yl)-carbamic acid 2,2,2-trichloro-ethyl ester 319
17 (5-Isopropyl-thiazol-2-yl)-carbamic acid 2,2,2-trichloro-ethyl ester 319
18 (5-tert-ButyI-thiazol-2-yl)-carbamic acid 2,2,2-trichloro-ethyl ester 333
19 (4-tert-Butyl-thiazol-2-yl)-carbamic acid 2,2,2-trichloro-ethyl ester 333
20 (4-Trifluoromethyl-pyridin-2-yl)-carbamic acid 2,2,2-trichloro-ethyl ester 339
21 (4-sec-Butyl-pyridin-2-yl)-carbamic acid 2,2,2-trichloro-ethyl ester 327

Preparation 22
3-Iodo-7-chloro-imidazo[l,2,a]pyridine
To a solution of 7-chloro-imidazo[l,2,a]pyridine (6.10 g, 40 mmol) (Yamanaka,
Motosuke et al., Chemical & Pharmaceutical Bulletin (1991), 39(6), 1556-67) in dry
acetonitrile (100 mL), add N-iodosuccinamide. Stir for 30 minutes. Filter off the
precipitate and then wash with acetonitrile. Recrystallize the precipitate from acetonitrile
to give a white solid. Concentrate the filtrate, dilute with ethyl acetate, wash with 10%
sodium hydrogensulfite (NaHSO3), saturated aqueous sodium bicarbonate, saturated
aqueous NaCl, dry over MgSO4, filter and evaporate. Use the combined solid without
further purification (8.0 g, 73%). 1H NMR (DMSO) 5 8.33 (d, 1H, J = 7.3 Hz), 7.79 (d,
1H, J = 2.0 Hz), 7.72 (s, 1H), 7.07 (dd, 1H, j = 7.3 and 2.0 Hz).
Preparation 23
4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyrazole-l-suifonicacid
dimethylamide
A. Pyrazole-1-sulfonic acid dimethylamide
Dissolve 4-iodopyrazole 9.24 g, 48.0 mmol) in THF (100 mL) and add NaH (2.26
g, 63.6 mmol, 60% in oil) is portionwise and stir for 30 minutes at 0 °C. Add dimethyl
sulfamoyl chloride (6.18 mL, 57.6 mmol) dropwise and stir 1 hour at 0 °C and 1 hour at
room temperature. Quench the reaction with saturated NaHCO3 solution and extract with
CH2Cl2, dry over anhydrous MgSO4, filter and concentrate. Chromatograph the residue
with hexanes/ethyl acetate 1:0 to 2:1 to give a clear oil (11.8 g, 82% yield). MS (ES), m/z
176 (M+l).

WO 2006/091671 PCT/US2006/006283
27
B. 4-(4,4,5,5-Tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-pyrazole-1 -sulfonic acid
dimethylamide
Combine pyrazole-1 -sulfonic acid dimethylamide (7.0 g, 23.2 mmol), potassium
acetate (6.3 g, 69.8 mmol), bis(pinacolato)diboron (6.5 g, 25.5 mmol), and DMSO (140
mL) and de-gas under a stream of nitrogen. Add PdCl2(dppf)CH2Cl2 (0.51 g, 0.70 mmol
and heat the reaction to 80 °C overnight. Dilute the reaction with water and extract with
ethyl acetate. Wash the combined organics with water and dry over anhydrous MgSO4,
filter and concentrate. Use the title compound contaminated by a 33% impurity of the
bipyrazole as a mixture.
Preparation 24
4-Bromo-2-ethyl-pyridine
Prepare the title compound according to the general procedure described in
Journal Organic Cliemistry, VoL 50, No. 22,1985, page 4410-4411. Slurry 4-
bromopyridine hydrochloride (4.17 g, 0.021 mol) in THF (100 mL) and cool to -78 °C
under nitrogen. Add ethylmagnesium bromide (15.7 mL of a 3.0 M solution in diethyl
ether, 2.2 equiv.) dropwise via syringe. Stir the reaction at -78 °C for 10 minutes then
remove the ice bath and allow the reaction to warm to room temperature. Quench
reaction with 20% ammonium chloride (aq) then dilute with diethyl ether. Wash organics
with water, 1 N HC1 (aq), then aqueous saturated sodium chloride. Dry organics over
magnesium sulfate, filter and concentrate in vacuo. Redissolve the residue in toluene
(100 mL) and place under nitrogen. Dissolve tetrachloro-l,2-benzoquinone (5.8 g, 1.1
equiv.) in acetic acid (50 mL) and add dropwise to the reaction. Allow reaction to stir
overnight at room temperature. Make the mixture basic by adding 1 N NaOH (aq) then
extract with ethyl acetate. Acidify organic layer with 1 N HC1 (aq) and extract with ethyl
acetate. Set organics aside. Basify the aqueous layer with 1 N NaOH (aq) and extract
with DCM. Wash this organic layer with aqueous saturated sodium chloride then dry
over magnesium sulfate. Filter and concentrate in vacuo to give a brown residue (2.64 g,
66%). LCMS (ES), m/z 188 (M+l, bromide pattern).

WO 2006/091671 PCT/US2006/006283
28
Prepare the following according to the same procedure as Preparation 24.

Preparation Name Physical DataMS (ES), m/z(M+l)
25 4-Bromo-2-isopropyl-pyridine 202 (M+l, bromide pattern)
Preparation 26
l-(4-Chloro-pyridin-2-yl)-propan-2-one
Make the title compound with a procedure similar to Preparation 162 A below
using 4-chloro-2-methylpyridine. MS(ES), m/z 170 (M+l).
Preparation 27
3-Iodo-7-pyridin-2-yl-imidazo[l,2-a]pyridine
A. 7-Pyridin-2-yl-imidazo[l,2-a]pyridine
To a round bottomed flask add 7-chloro-imidazo[l,2-a]pyridine (0.25 g, 1.6
mmol), tricyclohexylphosphine (55 mg, 0.12 equiv.), potassium acetate (0.24 g, 1.5
equiv.), bis(pinacolato)diboron (0.46 g, l.l equiv.) and dioxane (10 mL). Deoxygenate
this mixture thoroughly with N2 then add tris(dibenzylideneacetone)dipalladium (0) (75
mg, 0.05 equiv.) and heat the reaction to 80 °C overnight under N2. Filter the reaction
thru Celite® and wash with DCM then concentrate to dryness. To this residue, add 2-
bromopyridine (0.14 mL, 1.5 mmol), S-Phos (75 mg, 0.125 equiv.), potassium phosphate
(0.62 g, 2 equiv.), dioxane (10 mL), and water (5 mL). Deoxygenate this mixture
thoroughly with N2, add palladium (II) acetate (16 mg, 0.05 equiv.), and reflux the
reaction overnight. Concentrate the reaction to dryness and slurry in DCM. Filter this
slurry thru Celite® and wash with DCM. Concentrate the filtrate then purify by silica
column (EtOAc to 5% MeOH : DCM) to give a residue (0.325 g, >100 %). MS (ES), m/z
196 (M+l).

WO 2006/091671 PCT/US2006/006283
29
B. 3-Iodo-7-pyridin-2-yl-imidazo[l,2-a]pyridine
Dissolve 7-pyridin-2-yl-imidazo[l,2-a]pyridine (0.3 g, 1.5 mmol) in absolute
ethanol (10 mL) and add NIS (0.35 g, 1 equiv.). Heat the reaction to 50 °C for 30
minutes under N2 then dilute with ethyl acetate. Wash the organic layer with 1 N NaOH
followed by sat NaCl. Dry the organic layer over magnesium sulfate, filter and
concentrate to give a light tan solid (0.4 g, 82%). MS (ES), m/z 322 (M+l).
Prepare the following according to procedures similar to Preparation 27:

Preparation Name PhysicalData MS(ES), m/z(M+l)
28 - 3-Iodo-7-(2-methyl-2H-[l,2,4]triazol-3-yl)-imidazo[l,2-a]pyridine 326
29 3-Iodo-7-(2-memyl-pyridin-4-yl)-imidazo[ 1,2-a]pyridine 336
30 7-(3-Fluoro-pyridin-4-yl)-3-iodo-imidazo[l,2-a]pyridine 340
31 7-(2-Chloro-pyridin-4-yl)-imidazo[l,2-a3pyridine 232
32 7-[2-(3,3-Diethoxy-propyl)-pvridin-4-yl]-3-iodo-irnidazo[l,2-a]pyridine 452
33 3-Iodo-7-(2-isopropyl-pyridin-4-yl)-imidazo[l,2-a]pyridine 364
34 3-Iodo-7-(2-ethyl-pyridin-4-yl)-imidazo[l,2-a]pyridine 350
35 l-(4-Imidazo[ 1,2-a]pyridin-7-yl-pyridin-2-yl)-propan-2-one 252
36 3-Iodo-7-(pyridin-2-yl)-imidazo[l,2-a]pyridine 322
37 7-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine 210
Preparation 38
4-(3-Bromo-imidazo[l,2-a]pyridin-7-yl)-l-(3-piperidin-l-yl-propyl)-lH-pyridin-2-one
A. 4-Imidazo[ 1,2-a]pyridin-7-yl-1 H-pyridin-2-one
Prepare this intermediate by methods similar to Preparation 27 except using 4-
bromo-2-fluoro pyridine as a coupling partner MS(ES), m/z 214 (M+l). Heat the

WO 2006/091671 PCT/US2006/006283
30
intermediate 2-fluoropyridine in a round bottom flask with 5N HC1 under N2 atmosphere
to 80 °C for 2 hours. Cool, add 50 mL 2 M NH3 in MeOH and DCM transfer to
separatory funnel and extract with DCM (10 x). Filter aqueous layer and combine with
DCM extracts strip off DCM under reduced pressure to give 1.26 g (26% overall)
MS(BS),m/z 212(M+l).
B. 4-Imidazo[l,2-a]pyridin-7-yl-l-(3-piperidin-l-yl-propyl)-lH-pyridin-2-one
In a RBF under nitrogen, charge (850 mg, 4.0 mmols), l-(3-
chlororpropyl)piperine HC1 (1.18 g, 6 mmol), DMF (40 mL), and Cs2CO3 (2.8 g, 8.8
mmol), Nal (450 mg, 3 mmol) and heat to 78 °C for 24 hours. Filter the reaction and
rinse the solids with DCM. Combine DCM and filtrate and strip off under reduced
pressure then purify by passing through Varian SCX®,(10 g) column that is pre-washed
with water and methanol, the product being eluted with (20%) 2 N NH3 in methanol/
(80%) DCM. Evaporate solvent from the product containing fractions under reduced
pressure. Chromatograph using (40 g ISCO®) S1O2 eluting with a gradient of 0% to
10% 2 M NH3 in MeOH with the balance DCM. Evaporate solvents to afford ivory solid
410 mg (30%) MS(ES), m/z 337 (M+l).
C. 4-(3-Bromo-imidazo[l,2-a]pyridin-7-yl)-l-(3-piperidin-l-yl-propyl)-lH-pyridin-
2-one
Prepare the title compound in a similar fashion as in Preparation 78 B with the
exception that EtOH and acetonitrile are used as solvents. MS(ES), m/z 415,417 Br
isotopes (M+l).
Preparation 39
7-[2-(3,3-Diethoxy-propyl)-pyridin-4-yl]-imidazo[l,2-a]pyridine
In a round bottomed flask, add 9-BBN (0.5 M in THF, 42.2 mL, 2 equiv.) under
nitrogen. Add acrolein diethyl acetal (3.4 mL, 2.1 equiv.) via syringe and stir at room
temperature overnight. In a separate flask on the second day, combine 7-(2-chloro-
pyridin-4-yl)-imidazo[l,2-a]pyridine (2.42 g, 11 mmol), potassium phosphate (4.47 g, 2
equiv.), S-Phos (0.54 g, 12.5 mol %), dioxane (90 mL), and water (45 mL). De-gas with
nitrogen then add palladium (II) acetate (0.118 g, 5 mol %) under nitrogen. To this

WO 2006/091671 PCT/US2006/006283
31
solution add the material from the first flask via canula. Heat the reaction at 80 °C for 5.5
hours. Concentrate to dryness. Slurry in DCM then filter to remove insoluble material.
Wash with DCM. Concentrate filtrate and purify by silica plug (1:1 Hexanes : Ethyl
Acetate -> Ethyl Acetate -> 5% Methanol: DCM -> 10% Methanol: DCM) to give a
residue.(4.15 g, >100 %) which is used as is for the next step. MS (ES), m/z 326 (M+l).
Preparation 40
7-[2-(2-Morpholin-4-yl-propyl)-pyridin-4-yl]-imidazo[l,2-a]pyridine
Dissolve l-(4-imidazo[l,2-a]pyridin-7-yl-pyridin-2-yl)-propan-2-one (3.9 g, 15.5
mmol) in methanol (400 mL) under nitrogen. Add morpholine hydrochloride (38.4 g, 20
equiv.) followed by 3 A Sieves (7.8 g, powdered and dried in a vacuum oven at 100 °C
overnight). Stir five minutes then add sodium cyanoborohydride (1.0 M in THF, 28 mL,
1.8 equiv.) via syringe and stir at room temperature for 5 days. Filter to remove insoluble
material, washing with methanol. Concentrate to dryness then make basic with 20%
NaOH (aq) and extract with ethyl acetate. Wash organics with aqueous saturated sodium
chloride then dry over MgSCU. Filter and concentrate then purify by silica gel (Ethyl
Acetate ® 5% Methanol: DCM ® 10 % Methanol: DCM ® 5% 2M NH3 in methanol:
DCM ® 10 % 2 M NH3 in Methanol: DCM) to give product as a tan solid (3.7 g, 74%).
MS (ES), m/z 323 (M+l).
Prepare the following using procedures similar to Preparation 40:

Preparation Name Physical DataMS (ES), m/z(M+l)
41 2-(4-Imidazo[ 1,2-a]pyridin-7-yl-pyridin-2-yl)- 1-methyl-ethylamine 253
Preparation 42
[2-(4-Imidazo[l,2-a]pyridin-7-yl-pyridin-2-yl)-l-methyl-ethyl]-carbamic acid tert-butyl
ester
Dissolve 2-(4-imidazo[l,2-a]pyridin-7-yl-pyridin-2-yl)-l-methyl-ethylamine (0.1
g, 0.4 mmol) in a mixture of THF (10 mL) and DCM (10 mL) under nitrogen. Add di-

WO 2006/091671 PCT/US2006/006283
32
tert-butyl-dicarbonate (0.095 g, 1.1 equiv.)- Stir 45 minutes at room temperature then
dilute with ethyl acetate. Extract organics with water, 1 N NaOH (aq), then aqeuous
sodium chloride. Dry organics over MgSO4, then filter and concentrate. Purify by silica
gel (10 % Methanol: DCM) to give product (0.125 g, 89 %). MS (ES), m/z 353.2 (M+l).
Preparation 42A
3-Iodo-7-(4-methanesulfonyl-phenyl)-imidazo[ 1,2-a]pyridine
A. 7-(4-Methanesulfonyl-phenyl)-imidazo[l,2-a]pyridine
Heat a mixture of 7-chloro-imidazo[l,2-a] pyridine (100 g, 152.5 mmol, 1 eq), 4-
methylsulfonylphenyl boronic acid (157.3 g, 786.8 mmol, 1.2 eq), Pd(PPh3)4 (19 g, 16.3
mmol, 0.025 eq) and cesium carbonate (472.4 g, 1.44 mol, 2.2 eq) in a mixture of
anhydrous DME (2000 mL) and EtOH (1000 mL) at 80 °C under N2 atmosphere for 24
hours. Cool the mixture to room temperature and filter through Celite® to remove Pd
catalyst. Add water (5000 mL) alid extract this solution with CH2C12 (3x2000 mL). Dry
the organic phase over MgSO4 and evaporate. Add to the crude 2000 mL of CH2Cl2 and
heat to reflux. Remove insoluble materials by filtration and evaporate the solvent to
afford a yellow solid. Wash the solid with ethyl ether to give 150 g of the desired
compound as a light yellow solid. (Yield: 85%). MS (ES), m/z 273 (M+l).
B. 3-Iodo-7-(4-methanesulfonyl-phenyl)-imidazo[l,2-a}pyridine
Treat a solution of 7-(4-methanesulfonyl-phenyl)-imidazo[l,2-a]pyridine (101 g,
371.3 mmol, 1 eq) in 2000 mL of CH3CN at 0°C with NIS (83.5 g, 371.3 mmol, 1 eq).
Allow the mixture to stir at room temperature for 1 hour. Remove the solvent and the
dissolve the residue in 5000 mL of CH2C12, wash with 10% NaOH solution, NaHSO3
sat., water and aqueous saturated sodium chloride. Dry over MgSO4 and evaporate.
Triturate the solid obtained with hexanes, filter and dry in vacuo to afford 110 g of the
title compound as a yellow solid. (Yield: 75%). MS (ES), m/z 399 (M+l).
Preparation 43
4-(3-Iodo-imidazo[l,2-a]pyridin-7-yl)-benzoic acid methyl

WO 2006/091671 PCT/US2006/006283
33

Prepare the title compound using a similar procedure as the one for the
preparation of 3-iodo-7-(4-methanesulfonyl-phenyl)-imidazo[l,2-a]pyridine. MS(ES),
m/z 379 (M+l).
Preparation 44
4-[7-(4-Methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-
Combine 3-iodo-7-(4-methanesulfonyl-phenyl)-imidazo[l,2-a]pyridine (2.50 g,
6.28 mmol), (4-aminomethylphenyl)boronic acid, HC1 (1.29 g, 6.91 rnmol) and K2CO3
(3.47 g, 25.11 mmol) in 1,4-dioxane (30 mL) and water (15 mL). Bubble nitrogen
through the mixture for five minutes. Add dichlorobis(triphenylphosphine) palladium
(II) (0.132 g, 0.188 mmol). Attach a reflux condenser, and heat the mixture to 110 °C.
Stir overnight (15 hours), and cool to room temperature. Concentrate the mixture to
dryness in vacuo. Slurry the resulting solid into dichloromethane/methanol and filter
through Celite® 521. Concentrate the solution in vacuo to a yellow solid. Purify by
column chromatography (ethyl acetate ® 5% methanol in dichloromethane ® 10%
methanol in dichloromethane ® 10% 2 M NH3 in methanol in dichloromethane) to afford
product (1.57 g, 66%). MS(ES), m/z 378 (M+l).
Prepare the following according to Preparation 44:

Preparation Compound Name PhysicalDataMS(ES),m/z (M+l)
45 4-[7-(4-Methanesulfonyl-phenyl)-imidazo[ 1,2-a]pyridin-3-yl]-phenylamine 364
46 4-(7-Pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenylamine 287
47 4-[7-(lH-[l,2,3]Triazol-4-yl)-imidazo[l,2-a]pyridin-3-yl]-phenylamine 277
48 4-[7-(2-Methyl-2H-[l,2,4]triazol-3-yl)-imidazo[l,2-a]pyridin-3-yl]-phenylamine 291
49 4-[7-(2-Methyl-2H-[l,2,4]triazol-3-yl)-imidazo[l,2-a]pyridin-3-yl] -benzylamine 305
50 4-(3-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-3-fluoro-phenyl}-imidazo[l,2-a]pyridin-7-yl)-benzoic acid 514
51 4-[3-(4-Amino-3-fluoro-phenyl)-imidazo[l,2-a]pyridin-7-yl]-benzoic acid 348
52 4-(7-Pyridin-3-yl-imidazo[l,2-a]pyridin-3-yl)-benzylamine 301

WO 2006/091671 PCT/US2006/006283

53 4-(7-Pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-benzylamine 301
54 4- [7-(2-Methyl-pyridin-4-yl)-imidazo[ 1,2-a]pyridin-3 -yl]-benzylamine 315
Preparation 55
4-(7-Pyridin-3-yl-imidazo[l,2-a]pyridin-3-yl)-phenylamine
A. 4-(7-Chloro-imidazo[l,2-a]pyridin-3-yl)-phenylamine
To a round bottomed flask add 7-chloro-3-iodo-imidazo[l,2-a]pyridine (3.0 g,
0.011 mol), add 4-(4,4,5,5-tetramethyl-l,3,2-djoxaborolan-2-yl)aniline (2.6 g, 1.1 equiv.),
potassium carbonate (4.5 g, 3 equiv.), dioxane (40 mL), and water (20 mL).
Deoxygenate this mixture thoroughly with N2 then add
dichlorobis(triphenylphosphine)palladium (II) (0.23 g, 0.03 equiv.) and reflux the
reaction overnight under N2. Concentrate the reaction to dryness and slurry in DCM.
Filter this slurry thru Celite® and wash with DCM. Concentrate the filtrate then purify
by silica plug (EtOAc to 5% MeOH : DCM to 10 % MeOH : DCM) to give a pale grey
solid (2.6 g, 100%). MS (ES), m/z 244 (M+l).
B. 4-(7-Pyridin-3-yl-imidazo[l,2-a]pyridin-3-yl)-phenylamine
To a round bottomed flask add 4-(7-chloro-imidazo[l,2-a]pyridin-3-yl)-
phenylamine (0.5 g, 2.1 mmol), pyridine-3-boronic acid (0.38 g, 1.5 equiv.), potassium
phosphate (0.87 g, 2 equiv.), 2-dicyclohexylphosphino-2',6'-dimethoxy-l,r-biphenyl
(also called S-Phos, 0.105 g, 0.125 equiv.), 1,4-dioxane (10 mL), and water (5 mL).
Deoxygenate this mixture thoroughly with N2 then add palladium (II) acetate (23 mg,
0.05 equiv.) and reflux the reaction overnight. Concentrate the reaction to dryness and
slurry in DCM. Filter this slurry thru Celite® and wash with DCM. Concentrate the
filtrate then purify by silica plug (EtOAc to 5% MeOH: DCM to 10 % MeOH : DCM) to
give a yellow solid (0.39 g, 66%). MS (ES), m/z 287 (M+l).

WO 2006/091671 PCT/US2006/006283
-35

Prepare the following according to procedures similar to Preparation 55
Preparation Compound Name Physical dataMS (ES), m/z(M+l)
56 4-(7-Pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-benzylamine 301
57 3-(7-Pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-benzylamine 301
58 [4-(7-Pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzyl]-carbamic acid tert-butyl ester 401
59 4-(7-Thien-3-yl-imidazo[l,2-a]pyridin-3-yl)-benzonitrile 302
60 3-(7-Thien-3-yl-imidazo[l,2-a]pyridin-3-yl)-benzonitrile 302
61 4-Imidazo[l,2-a]pyridin-7-yl-pyrazole-l-sulfonicacid dimethylamide 292
Preparation 62
4-(7-Thien-3-yl-imidazo[l,2-a]pyridin-3-yl)-benzylamine
Dissolve 4-(7-thien-3-yl-imidazo[l,2-a]pyridin-3-yl)-benzonitrile (0.087 g, 0.29
mmol) in THF (8 mL). To the solution add a BH3-Me2S solution (2 M, 1.0 mL, 2.0
mmol) at room temperature. Stir the solution for 15 minutes and then heat at 50 °C for
3.5 hours. Cool the mixture at 0 °C and acidify to pH = 1 slowly and stir for 30 minutes.
Make the reaction mixture basic with solid NaOH to pH = 12-14, followed by extraction
with ethyl acetate. Wash the extracts with saturated aqueous saturated sodium chloride,
dry over MgSO4, filter and evaporate to afford 0.070 g. MS(ES), m/z 306 (M+l).
Prepare the following according to procedures similar to Preparation 62:

Preparation Compound Name Physical dataMS(ES),m/z(M+l)
63 3-(7-Thien-3-yl-imidazo[l ,2-ajpyri din-3-yl)-benzylamine 306
Preparation 64
4-(7-Pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenylamine
A. 7-Pyridin-4-yl-imidazo[l,2-a]pyridine Method A:

WO 2006/091671 PCT/US2006/006283
36
Charge a 250 mL round bottom flask equipped with a magnetic stirrer,
temperature controlled heating mantle, under N2 atmosphere, condenser, with 7-chloro-
imidazo[l,2-a]pyridine (4.0 g, 26.2 mmol), 4-pyridyl boronic acid (3.54 g, 28.8 mmol 1.1
Eq), 2-dicyclohexylphosphino-2',6'-dimethoxy-l,r-biphenyl (600 mg) [X-Phos can be
used as an alternate ligand in this reaction], Pd(OAc)2 (145 mg), K3PO4 (11.1 g, 52.6
mmol), and dioxane: H2O 2:1 (170 mL). Warm the reaction while purging with a N2
needle, then heat to 65 °C for 18 hours. Cool the reaction to room temperature and
transfer to a separatory funnel and siphon off the bottom layer (25 mL). Add EtOAc and
evaporate the solvents under reduced pressure off. Take the solids up into EtOAc again,
and evaporate under reduced pressure to azeotrope off traces of water. Dissolve the
brown solid into CH2Cl2 and 5% MeOH and then chromatograph using SiO2 eluting with
a slow gradient of 0% to 10% of 2 M NH3 in MeOH with the balance CH2C12. Evaporate
the product fractions under reduced pressure to give a light yellow/tan solid 4.5 g (89%).
MS (ES), m/z 196 (M+l).
A. 7-Pyridin-4-yl-imidazo[l,2-a]pyridine Method B:
1) To a 250 mL round-bottom flask under nitrogen, charge 7-chloro-imidazo[l,2-
a]pyridine (5.07 g, 33.2 mmol, 1 eq), bis(pinacolato)diboron (10.18 g, 40.1 mmol, 1.2
eq), potassium carbonate (6.86 g, 49.6 mmol, 1.5 eq), Pd(OAc)2 (370 mg, 1.6 mmol, 0.05
eq), tricyclohexylphosphine (914 mg, 3.3 mmol, 0.10 eq), diglyme (50 mL), and water
(68 mL). Heat the reaction mixture to 100 °C for 24 hours, then stir over the weekend at
room temperature. Filter the mixture and rinse with 2 x 10 mL diglyme. Slurry the
solids in 50 mL water for 1 hour, then filter and rinse 2 x 10 mL water. Dry the wet cake
(-10 g) in vacuo at 60 °C overnight to give the title compound as a gray solid (6.54 g,
26.8 mmol, 81% yield) with a purity of 99.3% by HPLC.
2) To a 100 mL round-bottom flask with stir bar and condenser, under nitrogen,
charge 4-bromopyridine hydrochloride (3.98 g, 20.5 mmol, 1 eq), 7-(4,4,5,5-tetramethyl-
[l,3,2]dioxaborolan-2-yl)-imidazo[l,2-a]pyridine (5.47 g, 22.4 mmol, 1.1 eq), Pd(OAc)2
(90 mg, 401 mmol, 0.02 eq), triphenylphosphine (217 mg, 827 mmol, 0.04 eq), K3PO4
(8.6 g, 40.5 mmol, 2 eq), 1-propanol (36 mL), and water (12 mL). Heat this reaction

WO 2006/091671 PCT/US2006/006283
37
mixture to reflux (90 °C) overnight and then cool to room temperature. Separate the
layers and add 40 mL MTBE and 40 mL 1 M HC1 to the PrOH layer. Wash the aqueous
layer with 40 mL MTBE and rinse twice with 6 mL 1-propanol. Add methanol (4 mL) to
the aqueous layer, which is heated to 45 °C before adding 9 mL of 5 M NaOH. Cool the
reaction mixture, and seed at 25 °C. Filter the reaction mixture after 1.5 hours and rinse
with 2 x 4 mL water with 10% MeOH, then with 8 mL MTBE (to help get the water out
of the cake and ease drying). Dry the solids in vacuo at 60 °C. Isolate the title as a
yellow solid (2.90 g) in 73% yield with 98% purity by HPLC (at 215 nm).
B. 3-Iodo-7-pyridin-4-yl-imidazo[l,2-a]pyridine
Charge a 250 mL round bottom flask equipped with: a magnetic stirrer,
temperature controlled heating mantle, N2 atmosphere, with 7-pyridin-4-yl-imidazo[l,2-
alpyridine (3.35 g, 17.2 mmol), NIS (3.8 g, 16.8 mmol), EtOH (3A). Heat the reaction to
65 °C for 1 hour. This can be followed by SiO2 TLC (100% EtOAc). Add more MS (3.8
g, 16.8 mmol) and heat the reaction to 65 °C for 1 hour. Mix the reaction while cooling
in an ice bath for 30 minutes then filter and rinse the solids with MeOH. Air dry the
solids and vacuum oven dry at 40 °C to afford 4.59 g (83%). Additional product can be
obtained from the filtrate. MS (ES), m/z 322 (M+l).
C. 4-(7-Pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenylamine.
Charge a 250 mL round bottom flask equipped with a magnetic stirrer,
temperature controlled heating mantle, under a N2 atmosphere, condenser, with 3-iodo-7-
pyridin-4-yl-imidazo[ l,2-a]pyridine (4.95g, 15.4 mmol), 4-amino phenyl boronic acid
(1.07 g), 4-(4,4,5,5-tetramethyl-l,3,2-dioxanborolan-2-yl)aniline (2.69 g) [these
combined give (18.5 mmols 1.2 equivalents) total of boronic acid], dimethoxy ethane
(140 mL), 2 M K2CO3 (40 mL, 28.8 mmol, 1.1 eq), and Pd(PPh3)4 (836 mg). Warm the
reaction while purging with N2, then heat to 65 °C for 18 hours. Cool the reaction to
room temperature and transfer to a separatory funnel and siphon off the bottom layer (25-
30 mL). Evaporate the DME under reduced pressure off and take the residue up into
MeOH (1 L), and 2 M NH3 in MeOH (10 mL). Filter the solution to remove Pd(0) and
evaporate under reduced pressure to coat onto SiO2 gel. Vacuum dry the SiO2 and

WO 2006/091671 PCT/US2006/006283
38
chromatograph using SiO2 eluting with a gradient of 0% to 10% of 2 M NH3 in MeOH
with the balance CH2Cl2. Evaporate the solvents under reduced pressure affording a
bright yellow solid 2.6 g (60%). MS (ES), m/z 286 (M+l).
Prepare the following according to Preparation 64: ^

Preparation Compound name Physical dataMS (ES), ni/z(M+l>
65 4-(7-Chloro-imidazo[ 1,2-a]pyridin-3-yl)-phenylamine 244
66 4-(7-Chloro-imidazo[l,2-a]pyridin-3-yl)-benzylamine 258
67 4-(7-Thiazol-2-yl-imidazo[l,2-a]pyridin-3-yl)-benzylamine 307
68 3-Iodo-7-pyridin-3-yl-imidazo[l,2-a]pyridine 322
69 {2-[4-(3-Iodo-imidazo[l,2-a]pyridin-7-yl)-pyridin-2-yl]-l-methyl-ethyl}-carbamic acid tert-butyl ester 479
70 3-Iodo-7-(6-methyl-pyridin-3-yl)-imidazo[l,2-a]pyridine 336
Preparation 71
l-(5-Bromo-pyridin-2-yl)-3-(5-tert-butyl-isoxazol-3-yl)-urea
Dissolve (5-tert-butyl-isoxazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester
(0.480 g, 1.52 mmol, 1.0 eq.) and 5-bromo-pyridin-2-yl amine (0.263 g, 1.52 mmol, 1.0
eq.) in DMSO (2.0 raL). Add triethyl amine (0.22 mL, 1.52 mmol, 1.0 eq.). Stir the
reaction mixture at 80 °C for about 16 hours, cool, then dilute with diethyl ether (100
mL), wash with saturated aqueous saturated sodium chloride (2x20 mL), water (2x20
mL), dry, filter, and concentrate to produce a brown oil. Purify the oil by silica gel flash
chromatography employing a 0-10% gradient of ethyl acetate in dichloromethane to
furnish 0.302 g (58%) of the title compound as a brown solid. MS (ES), m/z 339, 341
(M+l).

WO 2006/091671 PCT/US2006/006283
39
Prepare the following according to procedures similar to Preparation 71:

Preparation Name Physical DataMS (ES), m/z(M+l)
72 l-(4-Bromo-phenyl)-3-(5-tert-butyl-2H-pyrazol-3-yl)-urea 339
The following intermediates are prepared using essentially the same procedure as
for Example 64 below:

Preparation Name Physical DataMS (ES), m/z(M+l)
73 l-(4-Bromo-2-fluoro-phenyl)-3-(5-tert-butyl-isoxazol-3-yl)-urea 356,358
74 l-(4-Bromo-2-flaoro-phenyl)-3-(5-tert-butyl-isothiazol-3-yl)-urea 372, 374
Preparation 75
{4-[7-(6-Fluoro-pyridin-3-yl)-imidazo[l,2-a]pyridin-3-yl]-benzyl}-carbamic acid tert-
butyl ester
A. [4-(7-Chloro-imidazo[l,2-a]pyridin-3-yl)-benzyl]-carbamic acid tert-butyl ester
Add to a suspension of 3-iodo-7-chloro-imidazo[l,2-a]pyridine (4.80 g, 17.2
mmol, 1.0 eq) in dioxane (90 mL) 2 M Na2CO3 (30 mL) and (4-aminomethylphenyl)-
boronic acid (3.88 g, 20.7 mmol, 1.2 eq.). Deoxygenate the mixture and fill with
nitrogen. Add tetrakis (triphenylphosphine) palladium (0.50 g, 0.43 mmol, 0.025 eq).
Deoxygenate the reaction mixture and fill with nitrogen. Stir the reaction mixture at
85 °C for three days. Add (Boc)20 (4.51g, 20.7 mmol, 1.2 eq.) and stir the mixture at
60 °C for 20 minutes. Concentrate the mixture to dryness in vacuo. Slurry the resulting
solid into dichloromethane/methanol and filter through Celite ® 521. Concentrate the
solution in vacuo to a yellow solid (5.60 g). Employ silica ge] flash chromatography

WO 2006/091671 PCT/US2006/00628J
40

using a 0-4% MeOH/DCM gradient to afford 4.50 g (12.6 mmol, 73%) of the title
compound as a slightly yellow solid as product. MS(ES), m/z 358 (M+l).
B. {4-[7-(6-Ruoro-pyridin-3-yl)-imidazo[l,2-a]pyridin-3-yl]-benzyl}-carbamic acid tert
butyl ester
Suspend [4-(7-chloro-imidazo[l,2-a]pyridin-3-yl)-benzyl]-carbainic acid tert-
butyl ester (1.90 g, 5.30 mmol, 1.0 eq.) in dioxane/water (2:1, 36 mL). Add 2-fluoro-5-
pyridine boronic acid (0.75 g, 5.30 mrnol, 1.0 eq.), K3PO4 (2.25 g, 10.6 mmol, 2.0 eq.),
and S-phos (0.272 g, 0.66 mmol, 0.125 eq.). Deoxygenate the mixture and fill with
nitrogen. Add Pd(OAc)2 ( 0.059 g, .265 mmol, 0.05 eq.). Deoxygenate the reaction
mixture and fill with nitrogen. Stir the reaction at 80 °C under nitrogen for 16 hours. A
white solid is formed after the solution is cooled down. Filter off the white solid, wash
with water (3x15 mL), EtOAc (3x15 mL). Collect the solid (1.50 g). Purify the filtrate
by silica gel flash chromatographfy with a 0-5% MeOH/DCM gradient to afford the title
compound (0.52 g) as a slightly yellow solid. Combine the chromatography product and
the filtered solids to give slightly yellow solid. (2.02 g, 4.83 mmol) MS(ES), m/z 419
(M+l).
Prepare the following according to procedures similar to Preparation 75:

Preparation Name Physical DataMS (ES),m/z (M+l)
76 {5-[3-(4-Amino-phenyl)-imidazo[l,2-a]pyridin-7-yl]-pyridin-2-yl} -dimethyl-amine 405
77 4-[7-(6-Fluoro-pyridin-3-yl)-imidazo[l12-a]pyridin-3-yl]-phenylamine 305
Preparation 78
4-(7-Thiazol-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenylamine
A. 7-thiazol-2-yl-imidazo[l ,2-a]pyridine
In a 500 mL round bottom flask, stir a suspension of 7-chloro-imidazo[l,2-
a]pyridine (7.5 g, 49.2 mmol) in 250 mL 1,4-dioxane with bis(pinacolato)diboron (13.74

WO 2006/091671 PCT/US2006/006283
41
g, 54.1 mmol, 1.1 eq), potassium acetate (7.24 g, 73.8 mmol, 1.5 eq) and
tricyclohexylphosphine (1.66 g. 5.9 mmol, 0.12 eq). Deoxygenate the resulting slurry
with two cycles of evacuation and bubbling nitrogen through the slurry for 10 minutes
each. Fit the flask with a reflux condenser and add tris(dibenzylidineacetone)dipalladium
(0) (2.25 g, 2.45 mmol, 0.05 eq) and stir the mixture under nitrogen at 80 °C overnight.
Filter the hot mixture over a ~1 cm pad of celite, wash with 50 mL 1,4-dioxane, then
concentrate the combined filtrate and wash to give a brown pasty solid. Suspend a
portion of the solid (32.8 mmol) in 80 mL of dioxane, combine with 41.25 mL of 2 M
aqueous sodium carbonate (82.5 mmol, 2.5 eq) and 2-bromothiazole (4.38 mL, 8.07 g,
49.2 mmol, 1.5 eq), then deoxygenate twice via evacuation and bubbling nitrogen
through the suspension. Add tetrakis (triphenylphosphine) palladium (1.89 g, 1.64
mmol, 0.05 eq), fit the flask with a reflux condenser and stir the mixture under nitrogen at
100 °C overnight. Filter the dark brown-black hot mixture through a 1 cm pad of
Celite®, wash with 50 mL dioxane, then apply the combined filtrate and wash equally to
three 25 g SCX Mega Bond-Eluttm SCX cartridges (Varian) each pre-washed with 200
mL 1:1 CH2Cl2MeOH. After loading with vacuum assist, wash each cartridge with 300
mL 1:1 CH2Cl2:Me0H, then elute with 160 mL 1:1 CH2C12:2 M NH3-MeOH.
Concentrate the combined eluates in vacuo and purify through a 330 g silica gel cartridge
using a 0 to 5% methanol gradient in dichloromethane. Concentrate the pooled clean
fractions and dry to yield 3 g (45%) of 7-thiazol-2-yl-imidazo[l,2-a]pyridine as a tan
solid. MS (ES) m/z 202, (M+l).
B. 3-Bromo-7-thiazol-2-yl-imidazo[l,2-a]pyridine
Dissolve 7-thiazol-2-yl-imidazo[l,2-a]pyridine (1.14 g, 5.66 mmol) in 25 mL
absolute ethanol, then add NBS (1.0 g, 5.66 mmol), stir the mixture at room temperature
for 15 minutes, dilute with 35 mL dichloromethane and apply to a 10 g SCX Mega
Bond-Elut™ cartridge (Varian) pre-washed with 150 mL 1:1 CH2Cl2:Me0H. Wash the
SCX cartridge with 300 mL 1:1 CH2Cl2:Me0H, elute with 150 mL CH2C12:2 M NH3-
MeOH, and concentrate the eluates and dry to provide 1.07 g (67%) of the title
compound as a tan solid. MS (ES) 280, 282.

WO 2006/091671 PCT/US2006/006283
42
C. 4-(7-Thiazol-2-yl-imidazo[l,2-a]pyridin-3-yl)phenylamine
Take up 3-bromo-7-thiazol-2-yl-imidazo[l,2-a]pyridine (1.07 g, 3.82 mmol) and
4-aminophenylboronic acid hydrochloride (793 mg, 4.58 mmol, 1.2 eq) in 15 mL of
dioxane and 7 mL of 2 N aqueous sodium carbonate, then deoxygenate with
vacuum/nitrogen bubbling as described above. Add tetrakis (triphenylphosphine)
palladium (0) (221 mg, 0.19 1 mmol, 0.05 eq), fit the reaction flask with a reflux
condenser and heat the mixture to 95 °C with stirring under nitrogen for approximately 16
hours. Cool the dark brown reaction mixture, dilute with ethyl acetate (-40 mL) and
partition the layers in a separatory funnel. Dry the organic layer over solid magnesium
sulfate, filter, then apply to a 10 g SCX Mega Bond-Elut™ cartridge (Varian) prewashed
with 100 mL 1:1 CH2Cl2:MeOH. After loading, wash the cartridge with another 200-250
mL of the CH2Cl2:MeOH solution, then elute the product with 100 mL of CH2C12:2 M
NH3-MeOH, concentrate to a brown-orange oil, and purify via flash chromatography
with a gradient of 0 to 5% methanol in dichloromethane. Pool the clean fractions and
concentrate to provide 750 mg (67%) of the title compound as a yellow-brown solid after
drying. MS (ES) m/z 293 (M+l).
Preparation 79
2-Chloro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenylamine
A. 2-Chloro-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenylamine
Dissolve 4-bromo-2-chloro-phenylamine (4.2 g, 20 mmol) in dioxane (80 mL) in
a RBF under nitrogen. Add triethylamine (10 mL, 3.6 equiv.) then sparge with nitrogen
to de-gas. Add 4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (8.5 mL, 2.9 equiv.) dropwise
via syringe over approximately 5 minutes. Sparge an additional 5 minutes with nitrogen
then add [l,r-Bis(diphenyl-phosphino)ferrocene] dichloropalladium(II) (0.603 g, 3.7
mol %, 1:1 complex with dichloromethane). Place under nitrogen and heat at 80 °C
overnight. After the reaction cools, filter via Celite® washing with hexanes. Concentrate
filtrate to dryness and use crude.
B. 2-Chloro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenylamine

WO 2006/091671 PCT/US2006/006283
43
Combine 3-iodo-7-pyridin-4-yl-imidazo[l,2-a]pyridine (2.18 g, 6.8 mmol), 2-
chloro-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenylamine (crude material
from previous step, excess), potassium carbonate (2.8 g, 3 equiv.), dioxane (30 mL), and
water (15 mL). De-gas thouroughly with nitrogen then add dichloro-
bis(triphenylphosphine) palladium (II) (0.143 g, 3 mol %). Heat reaction at 80 °C
overnight. Concentrate to dryness then slurry in DCM and filter via Celite®, washing
with DCM. Concentrate filtrate then purify by silica plug (Hexanes ®1:1 Hexanes :
Ethyl Acetate ® 2.5 % Methanol: DCM ® 5% Methanol: DCM) to give an orange-
yellow solid (1.42 g, 46%). MS (ES), m/z 321.1 (M+l).
Prepare the following according to procedures similar to the above:

Preparation Name Physical DataMS (ES), m/z(M+l)
80 4-(7-Pyridin-4-yl-imidazo[ 1,2-a]pyridin-3 -yl)-2-trifluoromethyl-phenylamine 355
81 4-[7-(2-Methyl-pyridin-4-yl)-imidazo[l,2-a]pyridin-3-yl]-2-trifluoromethyl-phenylamine 369
Preparation 82
3-{4-[7-(4-Methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-propionic
Combine 3-iodo-7-(4-methanesulfonyl-phenyl)-imidazo[l,2-a]pyridine (125.0
mg, 0.314 mmol, 1.0 equiv) with [4-(2-carboxyethyl)phenylboronic acid (122 mg, 0.628
mmol, 2.0 equiv) in the presence of tetrakis(triphenylphoshine)palladium (0) (36.3 mg,
0.031 mmol, 0.10 equiv), and sodium carbonate (99.8 mg, 0.942 mmol, 3.0 equiv) in
DME and water mixture (1:1) (4 mL) in a 2-5 mL reaction volume microwave vessel.
Seal the reaction vessel with a septum then place in the microwave cavity. Stir the
WO 2006/091671 PCT/US2006/006283
-101-
CH2CI2, and wash with 20 mL of water. Dry the organics and concentrate to give 0.90 g
(64%) of the title compound as a brown oil. MS (ES), m/z 217 (M+l).
B. 1 -(5-tert-Butyl-isoxazol-3-yl)-3- {4-[7-(6-dimethylaminornethyl-pyridin-3-yl)-
imidazo[l ,2-a]pyridin-3-yl]-phenyl }-urea
In a 100 mL round bottom short neck flask, stir a suspension of 4-(7-chloro-
imidazo[l,2-a]pyridin-3-yl)-phenylarnrne (1 g, 4.1 mmol, leq) in 30 mL of 1,4-dioxane
with bis(pinacolatojdiboron (1.56 g, 6.15 mmol, 1.5 eq), potassium acetate (1.2 g, 12
mmol, 3 eq) and 2-biphenyl-biscyclohexylphosphine (0.29 g. 0.82 mmol, 0.20 eq).
Deoxygenate the resulting slurry with two cycles of evacuation and bubbling nitrogen
through the slurry for 10 minutes each. Fit the flask with a reflux condenser, add
palladium acetate (0.046 g, 0.21 mmol, 0.05 eq), and stir the mixture under nitrogen at 80
°C overnight. Filter the hot mixture over a ~1 cm pad of Celite®, wash with 50 mL
methanol, and concentrate the combined filtrate and wash to give an intermediate
boronate ester as a brown pasty solid. Dissolve the solid in 60 mL of 1,4-dioxane/water
(1:1) and treat with (5-bromo-pyridin-2-ylmethyl)-dimethyl-amine (0.90 g, 3.6 mmol),
tetrakis(triphenyl-phosphine)palladium(0) (0.21 g, 0.18 mmol) and sodium carbonate (1.1
g, 0.011 mmol). Deoxygenate the resulting slurry with two cycles of evacuation and
bubbling nitrogen through the slurry for 10 minutes each. Fit the flask with a reflux
condenser and stir the mixture under nitrogen at 80 °C overnight. Cool the reaction to
room temperature and bring to pH 5 with 1 N HC1. Apply the mixture to a 25 g SCX
Mega Bond-Elut1"1 SCX cartridge (Varian) pre-washed with 200 mL 1:1 CH2Cl2:MeOH.
After loading with vacuum assist, wash the cartridge with 300 mL 1:1 CH2Cl2:MeOH,
then elute with 160 mL 2 M NH3-MeOH. Concentrate the basic eluate in vacuo, and
dissolve the intermediate phenylamine in 30 mL of DMSO. Add triethylamine (0.50 g,
4.9 mmol) and (5-tert-butyl-isoxazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (1.3
g, 4.1 mmol), deoxygenate the mixture with N2 for 5 min, and heat at 70 °C overnight.
Cool the reaction to room temperature and bring to pH 5 with 1 N HC1. Apply the
mixture to a 25 g SCX Mega Bond-Eluttmcartridge (Varian) pre-washed with 200 mL 1:1
CH2Cl2:Me0H. After loading with vacuum assist, wash the cartridge with 300 mL 1:1
CH2Cl2:Me0H, then elute with 160 mL 2 M NH3-MeOH. Concentrate the basic eluate in

WO 2006/091671 PCT/US2006/006283
-102-
vacuo. Purify the resulting brown oil via reverse phase chromatography using a 25 cm by
50.8 mm (i.d.) column w/10 micron particles. Elute with MeCN/0.03%HCl H2O (5:95)
to 65:35 over 30 minutes gives 0.35 g of the title compound (17% overall). MS (ES), m/z
510 (M+l).
Example 160
(3-Trifluoromethyl-phenyl)-carbamic acid, 4-[7-(4-methanesulfonyl-phenyl)-
imidazo[l,2-a]pyridin-3-yl]-benzyl ester

A. [4-(7-Chloro-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-methanol
Charge a 50 mL round bottom flask equipped with: a magnetic stirrer,
temperature controlled heating mantle, N2 atmosphere, condenser, with 7-chloro-3-iodo-
imidazo[l,2-a]pyridine (1.0 g, 3.6 mmol), 4-(hydroxymethyl)phenyl boronic acid (570
mg, 3.75 mmol), 2 M K2CO3 (7 mL), dimethoxy ethane DME (25 mL). Deoxygenate
with a nitrogen purge and add Pd(TPP)4 (200 mg, 0.17 mmol 5 mol %) and heat the
reaction to 65 °C for 48 hours. Cool the reaction and siphon off the lower aqueous phase
(5 mL). Evaporate the reaction under vacuum at 42 °C to remove DME. Take up the
residue in CH2CI2 and wash with water (15 mL). Concentrate the CH2Cl2 and
chromatograph giving an oil mat solidified on standing to an ivory solid 670 mg (72 %)
MS (ES),m/z 259.1 (M+l).
B. {4-[7-(4-Methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-methanol
Charge a 100 mL round bottom flask equipped with: a magnetic stirrer,
temperature controlled heating mantle, N2 atmosphere, condenser, with [4-(7-chloro-
imidazo[l,2-a]pyridin-3-yl)-phenyl]-methanol (1.11 g, 4.3 mmol), 4-(methylsulfonyI)-

WO 2006/091671 PCT/US2006/006283
-103-
phenyl boronic acid (1.27 g, 6.4 mmol), 2-Dicyclohexyl-phosphino-2',6'-dimethoxy-
l,l'-biphenyl (236 mg), Pd(OAc)2 (60 mg), K3PO4 (3.6 g, 16.9 mmol), dioxane: H2O 2:1
(50 raL), EtOH-(3 A) (5 mL). Warm the reaction while purging with a N2 needle, then
heat to 65 °C for 18 hours. Cool the reaction to room temperature and siphon off the
bottom layer (8 mL). Evaporate the reaction under vaccuum and dissolve the residue into
warm MeOH and filter to remove Pd (0) solids. Rinse the solids with warm MeOHand
combine all the MeOHd. (total of 1 L). Evaporate the dissolved crude product under
vacuum with 20 g of SiO2 to dryness then chromatograph using SiO2 eluting with a
gradient of 0% to 10% of 2 M NH3 in MeOH with the balance CH2C12. Dry the product
in a vacuum oven at 40 °C for 24 hours to give a yellow solid 1.64 g (100.%) suspect
trapped solvent. MS (ES), m/z 379 (M+l).
C. (3-Trifluoromethyl-phenyl)-carbamic acid 4-[7-(4-methanesulfonyl-phenyl)-
imidazo[l,2-a]pyridin-3-yl]-benzyl ester
In a ice bath cooled 12 mL septum capped vial purged with N2 add {4-[7-(4-
methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-methanol (32 mg, 0.084
mmol) in CH2C12 (4 mL). Charge the vial with (aaa)-trifiuoro-m-tolyl-isocyanate (15.7
mg, 0.012 mL, 0.084 mmol). Remove the reaction from the ice bath and mix at room
temperature. Give the reaction a second charge of (aaa)-trifluoro-m-tolyl-isocyanate
(15.7 mg, 0.012 mL, 0.084 mmol) and heat to 35 °C for 6 hours. Chromatograph the
crude reaction using SiO2 eluting with a gradient of 0% to 8% of 2 M NH3 in MeOH with
the balance CH2C12. Dry the product in a vacuum oven at 40 °C for 24 hours to give the
title compound 23.5 mg (49%). MS (ES), m/z 566 (M+l).
Example 161
l-[5-(7-Pyridin-4-yl-irddazo[l,2-a]pyridin-3-yl)-pyridin-2-yl]-3-(m-trifluoromethyl-
phenyl)-urea


WO 2006/091671 PCT/US2006/006283
-104-
A. l-(5-Bromopyridin-2-yl)-3-(m-trifluororaethylphenyl)-urea
To a solution of 5-bromopyridin-2-yl amine (1.190 g, 6.88 mmol, 1.0 eq.) in THF
(20 mL), add 3-trifluoromethylphenyl isocyanate (0.96 mL, 6.88 mmol, 1.0 eq.) in a
drop-wise manner at room temperature. Stir the reaction mixture at room temperature for
30 minutes. Filter the solid and wash with MeOH (2x10 mL). Dry the solid to afford
1.81 g (5.0 mmol, 73%) of the title compound. MS (ES), m/z 360, 362 (M+l).
B. l-[5-(7-Pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-pyridin-2-yl]-3-(m-trifluoromethyl-
phenyl)-urea
To a solution of l-(5-bromopyridin-2-yl)-3-(m-trifluoromethylphenyl)-urea
(0.520 g, 1.44 mmol, 1.0 eq.) in dioxane (12 mL), add bis (pinacolato)diboron (0.410 g,
1.59 mmol, 1.1 eq.), tricyclohexylphosphine (0.048g, 12mol%), potassium acetate (0.211
g, 1.5 eq.), and tris(dibenzylidineacetone)dipalladium (0) (0.066 g, 5 mmol %).
Deoxygenate the reaction mixture and stir under nitrogen at 80 °C for approximately 16 h
and cool to room temperature. Add 3-iodo-7-pyridin-4-yl-imidazo[l,2-a]pyridine (0.460
g, 1.44 mmol, 1.0 eq.), sodium carbonate solution (2 M, 3 mL) and
tetrakis(triphenylphosphine)palladium (0) (0.083 g, 5 mmol %). Deoxygenate the
reaction mixture and stir at 80 °C for 6 hours, cool, then purify on a SCX cartridge
(Varian) as in Example 115. Concentrate SCX-eluted materials and purify via silica gel
flash chromatography employing a 0-4% gradient of methanol in dichloromethane to
afford 0.450 g (0.99 mmol, 69%) of the title compound. MS (ES), m/z 475 (M+l).
Prepare the following according to procedures similar to Example 161:

Ex. Compound Name PhysicalDataMS(ES)(m/z)
162 l-[5-(7-Thiazol-2-yl-imidazo[l,2-a]pyridin-3-yl)-pyridin-2-yl]-3-(m-trifluorornethyl-phenyl)-urea 481 (M+l)

WO 2006/091671 PCTAJS2006/006283
-105-

163 l-(5-tert-butyl-isoxazol-3-yl)-3-[5-(7-pyridin-4-yl-irnidazo[l,2-a]pyridin-3-yl)-pyridin-2-yl]-urea 454 (M+l)
164 l-(5-tert-butyl-isoxazol-3-yl)-3-[5-(7-thiazol-2-yl-imidazo[l,2-a]pyridin-3-yl)-pyridin-2-yl]-urea 460 (M+l)
Example 165
l-(4-{7-[2-(4-Methyl-piperazin-l-yl)-pyrimidin-5-yl]-imidazo[l,2-a]pyridin-3-yl}-
phenyl)-3-(3-trifluoromethyl-phenyl)-urea

A. 3-(4-Nitro-phenyl)-7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-imidazo[l,2-
a]pyridine.
Combine 7-chloro-3-(4-nitro-phenyl)-imidazo[l,2-a]pyridine (0.417 g, 1.52
mmol), bis(pinacolato)diboron (0.426 g, 1.68 mmol), tricyclohexylphosphine (0.051 g,
0.183 mmol) and potassium acetate (0.224 g, 2.29 mmol) in 1,4-dioxane (20 mL).
Bubble nitrogen through the mixture for five minutes. Add tris(dibenzylideneacetone)
dipalladium(0) (0.070 g, 0.076 mmol). Heat the mixture to 80 °C, stir overnight (15 hr),
and cool to room temperature. Filter the mixture through Celite® 521, and concentrate
the resulting solution to an orange oil, which is used as is (crude). MS(ES), m/z 366
(M+l).
B. 7-[2-(4-Methyl-piperazin-l-yl)-pyrirnidin-5-yl]-3-(4-nitro-phenyl)-irnidazo[l,2-
a]pyridine
Combine 3-(4-nitro-phenyl)-7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-
imidazo[l,2-a]pyridine (0.556 g, 1.52 mmol), 5-bromo-2-(4-methyl-piperazin-l-yl)-
pyrimidine, HC1 (0.447 g, 1.52 mmol) and potassium carbonate (0.842 g, 6.09 mmol) in
1,4-dioxane (20 mL) and water (10 mL). Bubble nitrogen through the mixture for five
minutes. Add dichlorobis(triphenylphosphine) palladium(II) (0.032 g, 0.046 mmol).
Attach a reflux condenser, and heat the mixture to 110 °C, stir overnight (15 hours), and
cool to room temperature. Concentrate the mixture to dryness in vacuo. Slurry the

WO 2006/091671 PCT/US2006/006283
106
resulting solid into dichloromethane/methanol and filter through Celite® 521.
Concentrate the solution in vacuo. Purify by column chromatography (ethyl acetate →
10% methanol in dichloromethane) to afford product (0.372 g, 59%, two steps). MS(ES),
m/z 416 (M+l).
C. l-(4-{7-[2-(4-Methyl-piperazin-l-yl)-pyrimidin-5-yl]-inudazo[l,2-a]pyridin-3-yl}-
phenyl)-3-(3-trifluoromethyl-phenyl)-urea
Combine 7-[2-(4-Methyl-piperazin-l-yl)-pyrimidin-5-yl]-3-(4-nitro-phenyl)-
imidazo[l,2-a]pyridine (0.318 g, 0.765 mmol), iron(IH) chloride (0.006 g, 0.038 mmol),
and 1,1-dimethylhydrazine (0.58 mL, 7.65 mmol) in methanol (10 mL). Attach a reflux
condenser, and heat the mixture to 70 °C, stir overnight (15 hours), and cool to room
temperature. Slurry the mixture into additional methanol and filter through Celite® 521.
Concentrate the solution in vacuo. Purify by column chromatography (ethyl acetate →
5% methanol in dichloromethane → 8% methanol in dichloromethane → 10% methanol
in dichloromethane) to afford a yellow solid intermediate amine, 4-{7-[2-(4-methyl-
piperazin-l-yl)-pyrimidin-5-yl]-imidazo[l,2-a]pyridin-3-yl}-phenylamine. Use as is.
MS(ES),w/z 386(M+l).
Combine the amine (0.164 g, 0.425 mmol), 3-trifluoromethylphenyl isocyanate
(0.060 mL, 0.425 mmol) and triethylamine (0.119 mL, 0.851 mmol) in DMSO (5 mL).
Stir the mixture at room temperature for ninety minutes. Extract the mixture with ethyl
acetate versus water. Wash the organic layer with saturated aqueous saturated sodium
chloride. Dry the resulting organics over magnesium sulfate, filter, and concentrate.
Purify by column chromatography (ethyl acetate → 5% methanol in dichloromethane →
10% methanol in dichloromethane) to afford product (0.056 g, 13%, two steps). MS(ES),
m/z 573 (M+l).
Example 166
l-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[2-(4-methyl-piperazin-l-yl)-pyrimidin-5-yl]-
imidazo[ 1,2-a]pyri din-3-yl} -phenyl)-urea

WO 2006/091671 PCT/US2006/006283
-107--

A. 7-[2-(4-Me1hyl-piperazin-l-yl)-pyrimidin-5-yl]-3-(4-nitro-phenyl)-iiaidazotl,2-
a]pyridine
Combine 3-(4-nitro-phenyl)-7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-
imidazo[l,2-a]pyridine (0.556 g, 1.52 mmol), 5-bromo-2-(4-methyl-piperazin-l-yl)-
pyrimidine, HC1 (0.447 g, 1.52 mmol) and potassium carbonate (0.842 g, 6.09 mmol) in
1,4-dioxane (20 mL) and water (10 mL). Bubble nitrogen through the mixture for five
minutes. Add dichlorobis(triphenylphosphine) palladium(II) (0.0.32 g, 0.046 mmol).
Attach a reflux condenser, and heat the mixture to 110 °C, stir overnight (15 hours), and
cool to room temperature. Concentrate the mixture to dryness in vacua. Slurry the
resulting solid into dichloromethane/methanol and filter through Celite® 521.
Concentrate the solution in vacuo. Purify by column chromatography (ethyl acetate →
10% methanol in dichloromethane) to afford product (0.372 g, 59%, two steps). MS(ES),
m/z 416 (M+l).
B. l-(5-tert-Butyl-isoxazol-3-yl)-3-(4- {7-[2-(4-methyl-piperazin- l-yl)-pyrimidin-5-yl]-
imidazo[l,2-a]pyridin-3-yl}-phenyl)-urea
Combine 7-[2-(4-methyl-piperazin-1 -yl)-pyrimidin-5-yl]-3-(4-nitro-phenyl)-
imidazo[l,2-a]pyridine (0.372 g, 0.895 mmol), iron(DI) chloride (0.007 g, 0.045 mmol),
and 1,1-dimethylhydrazine (0.68 mL, 8.95 mmol) in methanol (10 mL). Attach a reflux
condenser, and heat the mixture to 70 °C, stir overnight (15 hours), and cool to room
temperature. Slurry the mixture into additional methanol and filter through Celite® 521.
Concentrate the solution in vacuo to afford yellow solid intermediate amine, 4-{7-[2-(4-
memyl-piperazin-l-yl)-pyrimidin-5-yl]-imidazo[l,2-a]pyridin-3-yl}-phenylamine. Use
as is. MS(ES), m/z 386 (M+l)
Combine the amine (0.323 g, 0.838 mmol), (5-tert-butyl-isoxazol-3-yl)-carbamic
acid 2,2,2-trichloro-ethyl ester (0.291 g, 0.922 mmol) and triethylamine (0.128 mL, 0.922
mmol) in DMSO (10 mL). Heat the mixture to 70 °C, stir overnight, and cool to room
temperature. Extract the mixture with ethyl acetate versus water. Wash the organic layer

WO 2006/091671 PCT/US2006/006283
-108-
with saturated aqueous saturated sodium chloride. Dry the resulting organics over
magnesium sulfate, filter, and concentrate. Purify by column chromatography (ethyl
acetate → 10% methanol in dichloromethane → 10% 2 M NH3 in MeOH in
dichloromethane) to afford product (0.057 g, 11%, two steps). MS(ES), m/z 552 (M+l).
Example 167
N-(5-Methyl-thiazol-2-yl)-2-[4-(7-pyridin-4-yl-imidazo[l,2a]pyridine-3-yl)-phenyl3-
acetamide

A. [4-(7-Pyridin-4-yl-imidazo[l,2a]pyridine-3-yl)-phenyl]-acetic acid tert-butyl ester
Prepare using methods of example 219 (below) using 4-bromo-phenylacetic acid,
tert-butyl ester and 7-pyridin-4-yl-imidazo[l,2a]pyridine as coupling partners. Purify the
mixture with an SCX column using 1:1 CH2Cl2:MeOH /1:1 CH2C12:2N NH3-MeOH.
Concentrate the eluate to give a crusty yellow-orange solid and purify this solid on a 120
g silica cartridge with 100% CH2CI2 for 5 minutes, followed by a gradient of 0 →5%
MeOH in CH2Cl2 over 35 minutes. Pool and concentrate appropriate fractions to afford
the title compound as a yellow solid. MS (ES) m/z 386 (M+l).
B. [4-(7-Pyridin-4-yl-imidazo[l,2a]pyridine-3-yl)-phenyl]-acetic acid
Suspend [4-(7-pyridin-4-yl-imidazo[l,2a]pyridine-3-yl)-phenyl]-acetic acid tert-
butyl ester (370 mg, 0.96 mmol) in 10 mL of 4 N HCl/dioxane solution, add 1 mL water
and stir the resulting clear yellow solution overnight at room temperature. Concentrate to
dryness, dissolve in CH2Cl2:MeOH and purify on 10 g SCX cartridge by loading and
washing with 1:1 CH2Cl2:Me0H. Elute the free base with 1:1 CH2C12:2 N NH3-MeOH
and concentrate to dryness. LCMS (ES) m/z 330 (M+l).
C. N-(5-Methyl-thiazol-2-yl)-2-[4-(7-pyridin-4-yl-imidazo[l,2a]pyridine-3-yl)-phenyl]-
acetamide

WO 2006/091671 PCT/US2006/006283
-109--
Add [4-(7-pyridin-4-yl-ixnidazo[l,2a]pyridine-3-yl)-phenyl]-acetic acid (130 mg,
0.39 mmol) to 5 mL THF and 3 mL DMSO, warm briefly to 70 °C, then cool to room
temperature to give a slightly turbid yellow solution. Add 4-methyl morpholine (48mg,
52 mL, 0.47 mmol, 1.2 eq), 2-amino-5-methyl thiazole (54 mg, 0.47 mmol, 1.2 eq) and
stir for 10 minutes at room temperature. To this mixture, add DMTMM (131 mg, 0.47
mmol, 1.2 eq) and stir the heavy slurry at room temperature. Dilute the resulting orange
solution with 30 mL water, filter off and retain the flocculent solids. Dissolve the solid in
CH2C12 and minimal MeOH, purify on a 40 g silica cartridge 5 minutes at 100% CH2CI2
followed by a gradient of 0→5% MeOH in CH2Cl2 over 35 minutes. Pool, concentrate
and dry appropriate fractions to provide 75 mg of the title compound as a fluffy yellow
powder. LCMS (ES) m/z 426 (M+l).
Example 168
2-[2-Fluoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[3-(piperazine-l-
carbonyl)-5-trifluoromethyl-phenyl]-acetamide

A. 4-(3-{2-[2-Fluoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-
acetylamino}-5-trifluoromethyl-benzoyl)-piperazine-l-carboxylic acid tert-butyl ester
Prepare according to procedures similar to example 219 (below). MS (ES), m/z
703 (M+l).
B. 2-[2-Fluoro-4-(7-pyridin-2-yl-imidazo[l ,2-a]pyridin-3-yl)-phenyl]-N-[3-(piperazine-
l-carbonyl)-5-trifluoromethyl-phenyl]-acetamide
Dissolve 4-(3-{2-[2-fluoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-
acetylamino}-5-trifluoromethyl-benzoyl)-piperazine-l-carboxylic acid tert-butyl ester
(0.76 g, 0.108 mmol) in 1:1 CH2C12 MeOH (20 mL) and add 2M HC1 in THF (2 mL),
then stir 2 hours and concentrate in vacuo. Load onto a Varian MegaElut® SCX
cartridge (10 gram cartridge prewashed with methanol), rinse with methanol to remove
impurities then elute crude product with 2 M NH3 in methanol. Concentrate this solution

WO 2006/091671 PCT/US2006/006283
-110-
in vacuo then purify by silica gel chromatography (0%→ 10% 2 M NHsMethanol:
DCM) to give a yellow residue (0.400 g, 49 % over 2 steps). MS (ES), m/z 603 (M+l).
Example 169
4-[4-(7-Pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-
butyramide

Combine 4-[4-(7-Chloro-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-
trifluoromethyl-phenyl)-butyramide (0.15 g, 0.32 mmol), 4-pyridine boronic acid (0.04 g,
0.35 mmol), S-Phos (0.02 g, 0.04 mmol) and K3PO4 (0,13 g, 0.63 mmol) with dioxane
(3.5 mL) and water (1.5 mL) and stir at room temperature while the reaction contents are
de-gassed with nitrogen for 5 minutes. Add palladium diacetate (0.01 g, 0.04 mmol).
Heat to 100-105 °C for 20 hours. Cool and dilute with water (10 mL) and
dichloromethane. The organic layer are then filtered onto a pre-equilibrated in methanol
Varian SCX column (10 g), washed with 30 mL each of water, methanol,
dichloromethane and methanol. Elute crude product with 2N methanolic ammonia (50
mL). Concentrate the ammonia solution in vacuo to dryness to yield a residue that is
chromatographed on silica (0→3% methanol in ethyl acetate over 30 min) to yield 4-[4-
(7-Pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-
butyramide (0.10 g, 0.19 mmol). MS(ESI), m/z 501 (M+l).
Prepare the following according to procedures similar to Example 169:

WO 2006/091671 PCT/US2006/006283
-111-

Ex. Compound Name Physical DataMS(ES),(m/z)
170 2,-{4-[7-(2-Fluoro-pyridin-4-yl)-imidazo[l,2-a]pyridin-3-yl]-phenyl} -N-(3 -trifluoromethyl-phenyl)-acetamide 491 (M+l)
171 N-(5-tert-Butyl-isoxazol-3-yl)-2-{4-[7-(2-fluoro-pyridin-4-yl>imidazo[ 1,2-a]pyridin-3-yl]-phenyl} –acetamide 471 (M+l)
Example 172
N-(4-Cyano-3-trifluoromethyl-phenyl)-2-[4-(7-pyridin-4-yl-imidazo[l,2a]pyridine-3-yl)-
phenyl]-acetamide

Suspend 3-iodo-7-pyridin-4-yl-imidazo[l,2-a]pyridine (321 mg, 1 mmol), N-(4-
Cyano-3-trifluoromethyl-phenyl)-2-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-
phenyl]-acetamide (473 mg, 1.1 mmol) in 5 mL dioxane, add 2 M aqueous sodium
carbonate solution (1.25 mL, 2.5 mmol), deoxygenate by bubbling nitrogen gas through
the suspension for at least 15 minutes. Add tetrakis(triphenylphosphine)palladium(0) (58
mg, 0.05 mmol), fit flask with reflux condenser and heat at 70 °C for 16 hours under a
nitrogen atmosphere. Cool reaction mixture to room temperature, dilute with EtOAc (70
mL), wash with 20 mL aqueous saturated sodium chloride, separate layers and back-
extract the aqueous layer with 40 mL EtOAc. Combine organic layers, dry over MgSO4,
filter directly onto a 10 g SCX cartridge pre-washed with 1:1 dichloromethane:MeOH.
Wash and elute product from cartridge with 1:1 dichloromethane:MeOH and 1:1
dichloromethane:2 N NH3-MeOH, respectively, then concentrate the eluate in vacuo to
provide yellow oil. Purify the oil on a 40 g silica cartridge with 100% dichloromethane
for 5 minutes followed by a gradient of 0 -> 5% MeOH in dichloromethane over 35

WO 2006/091671 PCT/US2006/006283
minutes. Pool and concentrate clean fractions to afford 188 mg (37%) of the title
compound as yellow crystals. LCMS (ES) m/z 498 (M+l).
Example 173
2-[4-(7-Pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-
acetamide

Free base Method A, Form HI:
Charge 7-pyridin-4-yl-imidazo[l,2-a]pyridine (19.5 g, 100 mmol), 2-(4-bromo-
phenyl)-N-(3-trifluoromethyl-phenyl)-acetamide (35.8 g, 100 mmol), potassium acetate
(49.0 g, 500 mmol), tetrabutylammonium bromide (32.2 g, 100 mmol) and NMP (250
mL) into a 3L flask, at ambient temperature. Flush the flask with nitrogen and add
palladium acetate (1.1 g, 5 mol%) and tris-(2,4-di-t-butylphenyl)phosphite (3.2 g,
5mol%) were added. Flush the flask with nitrogen and heat to 120 °C for 2 hours. Allow
reaction to come to ambient temperature and add 250 mL water. Bring the solution to
pH=l with cone. HC1 and add 200 mL ethyl acetate. Separate the layers and bring the
aqueous layer to pH=10 with NaOH. Stir the slurry at ambient temperature overnight,
filter, wash with water, collect and dry under vacuum at 60 °C to afford 35.78 g of a
yellow solid. Purify the yellow solid on silica gel chromatography by eluting with
dioxane (63.5%)/heptane (34%)/2M ammonia in MeOH (2.5%). Further purify by
elution through a second silica gel column with THF (42%)/methylene chloride
(55.5%)/2M ammonia in MeOH (2.5%) to afford 30 g of the title compound as a yellow
solid (>99% purity by HPLC). Heat a portion of the title compound (5 g) at reflux in
acetonitrile (15 mL) for 30 minutes, then cool to ambient temperature. Stir the yellow
suspension at ambient temperature for 30 minutes, cool to 0 °C, filter, and dry under
vacuum at 60 °C to afford 4.77 g of a yellow solid having a melting point of 217 °C. 1H-

WO 2006/091671 PCT/US2006/006283
113

NMR (300 MHz, DMSO-d6) d 8.7(m, 3H), 8.25(s, 1H), 8.15(, 1H), 7.9(m, 3H), 7.7(d,
1H), 7.65(d, 2H), 7.55(m, 3H), 7.4(m, 2H), 3.8(s, 2H).
Preparation of Free base Form II polymorph
Heat2-[4K7-pyridin-^yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-
trifluoromethyl-phenyl)-acetamide (0.5 g) and methanol (5 mL) to reflux to give a
solution. Add water (approx. 2 mL) dropwise until the cloud point is reached. Continue
to heat and stir the gummy solid until the solid crystallizes. Cool the suspension to
ambient temperature over 45 min, then filter and dry in a vacuum oven at 60 °C to afford
0.47 g of the form II polymorph. mp 202 °C.
Preparation of Free Base Form I polymorph
Heat 2-[4-(7-pyridin-4-yf-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-
trifluoromethyl-phenyl)-acetamide (190 g) and methanol (1530 mL) to 60 °C with
stirring in a 5 L flask to give a solution. Add water (670 mL) slowly until the cloud point
is reached. Cool the cloudy solution to 50 °C, where an oil begins to separate from
solution. Allow the mixture to cool to ambient temperature and stir overnight (18 h) to
yield a suspension of crystals. Cool the suspension in an ice/water bath, filter, and dry in
a vacuum oven at 60 °C to afford 163 g of the form I polymorph. mp 193 °C.
Succinate Salt
Add 2-[4-(7-pyridin-4-yl-imidazo[l ,2-a]pyridin-3-yl)-phenyl]-iV-(3-
trifluoromethyl-phenyl)-acetamide (4.5 g, 9.4 mmol) to isopropyl alcohol (120 mL) and
heated to 80 °C to give a solution. Dissolve succinic acid (1.11 g, 9.4 mmol) in isopropyl
alcohol (15 mL) by heating to 80 °C. Combine the two solutions and concentrate to a
volume of 70 mL to give a suspension. Cool the suspension to 0 °C, filter and dry to
afford 4.7 g of the succinate salt as a yellow solid. Recrystallize 4.4 g of the crude
product from isopropyl alcohol (40 mL) to afford 3.66 g of a yellow solid. 1H-NMR

WO 2006/091671 PCT/US2006/006283
114
(300 MHz, DMS0-d6) d 2.40 (s, 4H), 3.76 (s, 2H), 7.37-7.88 (m, 11H), 8.11 (s, 1H), 8.22
(s, 1H), 8.66 (m, 3H), 10.56 (s, 1H), 12.12 (s, 2H).
Mono-hydrochloride Salt
Dissolve 2-[4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-
trifluoromethyl-phenyl)-acetamide (4.5 g, 9.4mmol) in refluxing isopropyl alcohol (80
mL), then add 5N HC1 (1.88 mL, 9.4 mmol) in one portion. Cool the mixture to 23 °C
and evaporate off the solvent to afford a non-crystalline solid. Suspend this solid in water
(100 mL) and heat with stirring to 90 °C, then allow tp cool to 23 °C and stir overnight.
Filter the suspension and dry to afford 3.75 g of the mono-HCl salt as a light orange
solid. 1H-NMR (300 MHz, DMSO-d6) 6 3.81 (s, 2H), 7.36-8.14 (m, 12H), 8.34 (s, 1H),
8.74 (m, 3H), 10.84 (s, 1H).
Free base Method B amorphous:
Suspend 3-iodo-7-pyridin-4-yl-imidazo[l,2-a)pyridine (0.39 g, 1.21 mmol), 2-[4-
(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-
acetamide (0.73 g, 1.80 mmol) and potassium carbonate (0.50 g, 3.63 mmol) in a solution
of dioxane (14 mL) and water (7 mL). Deoxygenate the reaction contents with nitrogen
for 10 minutes at room temperature. Add trans-Dichlorobis(triphenylphosphine)-
palladium (II) (22 mg, 0.03 mmol) to the reaction. Fit a reflux condenser and heat the
reaction to 105 °C for 3 hours. Cool the reaction and dilute with ethyl acetate (75 mL)
and separate the layers. Extract the aqueous layer with EtOAc (2 X 30 mL). Pool the
organics, dry over MgSO4 and filter onto a Varian SCX column (10 g) prewashed with
methanol. Elute the column with dichloromethane, 1:1 methanol/dichloromethane and
methanol (50 mL each). Elute the title compound with 2 N NH3/methanol (100 mL).
Concentrate the methanolic solution to dryness and chromatograph on silica using 8® 10
% methanol gradient in 1:1 ethyl acetate:dichloromethane over 45 minutes to give the
title compound (0.32 g, 54%). MS(ES), m/z 473 (M+l).
Prepare the following according to procedures similar to Example 173 Free base
Method B:

WO 2006/091671 PCT/US2006/006283
115

Ex. Compound Name Physical DataMS(ES)(m/z)
174 2- {4-[7-(4-Methanesulfonyl-phenyl)-imidazo[ 1,2-a]pyridin-3-yl]-phenyl} -N-(3-trifluoromethyl-phenyl)-acetamide 550 (M+l)
175 N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(7-pyridin-4-yl-imidazo[l,2-a3pyridin-3-yl)-phenyl]-acetamide 452 (M+l)
176 N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 465 (M+l)
177 N-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-2-[4-(7-thiazol-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 471 (M+l)
178 N-(5-tert-Butyl-[l,3,4]thiadiazol-2-yl)-2-[4-(7-pyridin-4-yl-imidazo[l,2-a(pyridin-3-yl)-phenyl]-acetamide 469 (M+l)
179 N-(5-tert-Butyl-[l,3,4]thiadiazol-2-yl)-2-[4-(7-thiazol-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 475 (M+l)
180 N-(5-tert-Butyl-[l,3,4]thiadiazol-2-yl)-2-{4-[7-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl} -acetamide 547 (M+l)
181 2-[4-(7-Pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(4-trifluoromethyl-pyridin-2-yl)-acetamide 474 (M+l)
182 2-{4-[7-(4-Methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-phenyl} -N-(4-trifluoromethyl-pyridin-2-yl)-acetamide 551 (M+l)
183 2-{4-[7-(6-Methyl-pyridin-3-yl)-imidazo[l,2-a]pyridin-3-yl]-phenyl} -N-(3-trifluoromethyl-phenyl)-acetamide 487 (M+l)
184 2- {4-[7-(2-Methyl-pyridin-4-yl)-imidazo[l ,2-a]pyridin-3-yl]-phenyl}-N-(3-trifluoromethyl-phenyl)-acetamide 487 (M+l)
185 2-[4-(7-Pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-acetamide 473 (M+l)
186 2-{2-Fluoro-4-[7-(2-methyl-pyridin-4-yl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-N-(3-trifluoromethyl-phenyl)-acetamide 505 (M+l)
187 2-[2-Ruoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-acetamide 491 (M+l)
188 2-[2-Huoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-acetamide 491 (M+l)
189 N-(4-Chloro-3-trifluoromethyl-phenyl)-2-{4-[7-(4-methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-phenyl} -acetamide 584
190 N-(4-Chloro-3-trifluoromethyl-phenyl)-2-[4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 507
191 2-[2-Chloro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-acetamide 507
192 N-(5-tert-Butyl-isoxazol-3-yl)-2-[2-chloro-4-(7-pyridin-4-yl-imidazori,2-a]pyridin-3-yl)-phenyl]-acetamide 486

WO 2006/091671 PCT/US2006/006283
116

193 2-[2-Chloro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(4-trifluoromethyl-pyridin-2-yl)-acetamide 508
194 N-(2-Fluoro-5-trifluoromethyl-phenyl)-2- {4-[7-(4-methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-phenyl }-acetamide 568 (M+l)
195 N-(5-tert-Butyl-isoxazol-3-yl)-2- {4-[7-(4-methanesulfonyl-phenyl)-imidazo[ 1,2-a]pyridin-3-yl]-phenyl} -acetamide 529 (M+l)
196 N-(5-tert-Butyl-isoxazol-3-yl)-2-{2-fluoro-4-[7-(4-methanesulfonyl-phenyl)-imidazo[l,2-a]pyridm-3-yl]-phenyl}-acetami de 547 (M+l)
197 N-(5-tert-Butyl-isoxazol-3-yl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide 470 (M+l)
198 N-(2-Fluoro-5-trifluoromethyl-phenyl)-2-[4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide 491 (M+l)
199 N-(5-tert-Butyl-isoxazol-3-yl)-2-[2-fluoro-4-(7-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide 470 (M+l)
200 2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(4-trifiuoromethyl-pyridin-2-yl)-acetamide 492 (M+l)
201 2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(4-isopropyl-pyridin-2-yl)-acetamide 466 (M+l)
202 2-[2-Fluoro-4-(7-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-N-(4-trifluoromethyl-pyridin-2-yl)-acetamide 492 (M+l)
Example 203
Prepare the following according to procedures similar to Example 126:

Compound Name Physical DataMS(ES),(m/z)
N-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(4-methanesulfonyl-phenyl)-imidazo[ 1,2-a]pyridin-3-yl]-phenyl}-propionamide 543 (M+l)
Example 204
2-[2-Amino-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(4-trifluoromethyl-
pyridin-2-yl)-acetamide

WO 2006/091671 PCT/US2006/006283
117

Suspend 2-[2-nitro-4-(7-pyridin4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(4-
trifluoromethyl-pyridin-2-yl)-acetamide (0.18 g, 0.35 nunol) and ammonium formate
(0.11 g, 1.82 mmol) in anhydrous methanol (5 mL) and bubble nitrogen through the
solution for 5 minutes. Under a positive stream of nitrogen, add 10 % Pd-on carbon
(0.03, 0.03 mmol) to the solution and stir the reaction at ambient temperature for 18
hours. Filter the reaction contents through a pad of Celite® and wash the pad with
methanol (40 mL). Concentrate the solution and then chromatograph the residue on silica
using a gradient of (0-^2->5 %) methanol in dichloromethane to yield the title compound
(0.03 g, 0.05 mmol). MS(ES), m/z 489 (M+l).
Example 205
N-[3-(l-Dimethylamino-l-methyl-ethyl)-phenyl]-2-[2-fluoro-4-(7-pyridin-4-yl-
imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide

A. (l-{3-[2-(4-Bromo-2-fluoro-phenyl)-acetylamino]-phenyl}-l-methyl-ethyl)-carbamic
acid tert-butyl ester
Dissolve (4-bromo-2-fluoro-phenyl) acetic acid (1.49 g, 6.39 mmol) in 25 mL
amylene-stabilized chloroform and add hydroxybenzotriazole hydrate (0.95 g, 7.03
mmol), to give a slurry. Add l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (1.47 g, 7.67 mmol) and stir the resulting clear solution at room
temperature for 15 minutes. Add [l-(3-amino-phenyl)-l-methyl-ethyl]-carbamic acid
tert-butyl ester and stir for 90 minutes at room temperature. Dilute reaction with 20 mL
dichloromethane and wash with saturated NaHCO3,1 N NaHSO4, and dilute aqueous
saturated sodium chloride, then dry over MgSO4 and concentrate to give a brittle tan

WO 2006/091671 PCT/US2006/006283
118
foam. Purify the foam on a 120 g silica cartridge with 100% CH2Cl2 for 5 minutes
followed by a gradient of 0® 10% EtOAc in CH2Cl2 over 40 minutes. Concentrate and
dry clean fractions to provide 2.11 g (71%) of the title compound as a brittle white foam.
LCMS (ES m/z 463/465 (M-l).
B. [l-(3-{2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-
acetylamino}-phenyl)-l-methyl-ethyl]-carbamic acid tert-butyl ester
Prepare with coupling methods as described in example 219 (below) with
l-{3-[2-(4-bromo-2-fluoro-phenyl)-acetylamino]-phenyl}-l-methyl-ethyl)-carbamic acid
tert-butyl ester (0.465 g, 1 mmol) and 7-pyridin-4-yl-imidazo[l,2a]pyridine (0.195 g, 1
mmol) to give 450 mg (77%) of the title compound as a yellow-green foam after flash
column chromatography. LCMS (ES) m/z 580 (M+l).
C . N-[3-(l-Amino-l-methyl-ethyl)-phenyl]-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[l,2-
a]pyridin-3-yl)-phenyl]-acetamide
Dissolve [l-(3-{2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[l,2a]pyridin-3-yl)-
phenyl]-acetylamino}-phenyl)-l-methyl-ethyl]-carbamic acid tert-butyl ester (450 mg,
0.77 mmol) in 2 mL dioxane and 1 mL water to give a clear yellow solution. Add 8 mL
of 4N HCl-dioxane solution and stir at room temperature 1-2 hours. Remove volatiles in
vacuo and free base the crusty yellow solid with a 10 g SCX cartridge. Concentrate SCX
eluates and purify by flash chromatography on a 40 g silica cartridge with 95:5
CH2Cl2:Me0H, then 95:5 CH2C12:2N NH3-MeOH. Concentrate pure fractions to yield
313 mg (84%) of the title compound as a pale yellow foam. LCMS (ES) m/z 480 (M+l).
D. Af-[3-(l-Dimethylamino-l-methyl-ethyl)-phenyl3-2-[2-fluoro-4-(7-pyridin-4-yl-
imidazo[ 1,2-a] pyridin-3 -yl)-phenyl] -acetamide
Dissolve N-[3-(l-amino-l-methyl-ethyl)-phenyl]-2-[2-fluoro-4-(7-pyridin-
4-yl-imidazo[l,2a]pyridin-3-yl)-phenyl]-acetarnide (185 mg, 0.385 mmol) in 3 mL
absolute ethanol, add sodium acetate (190 mg, 2.31 mmol) and paraformaldehyde (129
mg, 1.43 mmol) and stir together under nitrogen for 15 minutes at room temperature.
Add sodium cyanoborohydride (90 mg, 1.43 mmol) and stir under nitrogen for 16 hours

WO 2006/091671 PCT/US2006/006283
119
at room temperature. Dilute reaction mixture with 10 mL 1 N aqueous HC1 and stir the
clear yellow solution at room temperature for 15 minutes. Adjust the solution to pH ~8
with 1 N aqueous NaOH, extract twice with 20 mL portions of dichloromethane.
Combine organic layers, dry over MgSO4 and concentrate to give a yellow film. Purify
the film on a rotary chromatograph using a 1 mm thick disk and 93:7 CH2Cl2 :2N NH3-
MeOH as eluent. Concentrate and dry pure fractions to provide 131 mg (67%) of the title
compound as a yellow foam. LCMS (ES) m/z 508 (M+l).
Example 206
N-(5-tert-butyl-isoxazol-3-yl)-3-[3-(7-thiazol-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-
propionamide

A. 3-(3-Bromo-phenyl)-N-(5-tert-butyl-isoxazol-3-yl)-propionamide
Stir a solution of 3-(3-bromo-phenyl)-propionic acid (1.930 g, 8.43 mmol; 1.0 eq.)
3-amino-5-tert-butylisoxazole (1.299 g, 9.27 mmol, 1.1 eq.) in THF (30 mL) at room
temperature for 10 minutes. Add 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpho-
linium chloride (DMTMM, 2.56 g, 1.1 eq.) and N-methyl morpholine (0.1 mL) to the
mixture. Stir the reaction mixture at room temperature for about 16 hours, concentrate in
vacuo, then add DCM (100 mL), wash with saturated aqueous saturated sodium chloride
(2x20 mL) and water (2x20 mL), dry, filter and concentrate. Purify the concentrated
material by silica gel flash chromatography employing dichloromethane to furnish 1.25 g
(3.56 mmol, 42%) of the title amide as a white solid. MS (ES), m/z 351, 353 (M+l).
B.N-(5-tert-butyl-isoxazol-3-yl)-3-[3-(7-thiazol-2-yl-imidazo[l,2-a]pyridin-3-yl)-
phenyl]-propionamide
To a solution of 3-(3-bromo-phenyl)-N-(5-tert-butyl-isoxazol-3-yl)-propionarnide
(1.090 g, 3.1 mmol, 1.0 eq.) in DMSO (10 mL), add bis (pinacolato)diboron (0.794 g, 3.1

WO 2006/091671 PCT/US2006/006283
120
mmol, 1.0 eq.), potassium acetate (0.912 g, 3.0 eq.), and [l,I'-bis(diphenylphosphino)-
ferrocenejdichloropalladium (II) (0.068 g, 3 mmol %). Deoxygenate the reaction
mixture, stir under nitrogen at 80 °C for about 16 hours, and cool to room temperature.
Add diethyl ether (160 mL), wash with saturated aqueous saturated sodium chloride
(2x30 mL) and water (2x30 mL), dry, filter and concentrate to provide 1.30 g of a brown
solid. Dissolve a portion (0.370 g, 0.93 mmol, 1.0 eq.) of the solid in dioxane (20 mL),
then add 3-bromo-7-thiazol-2-yl-imidazo[l,2-a]-pyridine (0.260 g, 093 mmol, 1.0 eq.),
sodium carbonate solution (2 M, 4 mL) and tetrakis(triphenylphosphine)palladium (0)
(0.054, mmol %). Deoxygenate the reaction mixture with nitrogen and stir at 80 °C for
16 hours. The mixture is purified on a 5 g SCX column (Varian) as in Example 173.
Concentrate the SCX eluates and purify via silica gel flash chromatography using a 0-4%
methanol/dichloromethane gradient to supply 0.168 g (0.36 mmol, 40%) of the title
compound as a slightly yellow solid. MS (ES), m/z 472 (M+l).
Prepare the following according to procedures similar to Example 206:

Ex. Compound Name Physical DataMS(ES)(m/z)
207 N-(5-tert-butyl-isoxazol-3-yl)-3-[3-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-propionamide 466 (M+l)
208 N-(4-tert-butyl-6-methyl-pyridin-2-yl)-2-[4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 476 (M+l)
Example 209
N-(5-tert-Butyl-isoxazol-3-yl)-2-(4-{7-[4-(2-diethylamino-ethanesulfonyl)-phenyl]-
imidazo[l ,2-a]pyridin-3-yl }-phenyl)-acetamide

A. [2-(4-Bromo-benzenesulfonyl)-ethyl]-carbamic acid tert-butyl ester
Suspend (4-Bromobenzenesulfonyl)-acetonitrile (10.41 g, 40.02 mmol) in THF
and cooled to 0 °C, and add borane-dimethylsulfide complex (10 M, 12 mL, 120 mmol)
to the suspension which is allowed to slowly warm to ambient temperature. The next

WO 2006/091671 PCT/US2006/006283
121
day, quench the reaction with a slow addition of methanol until off-gassing ceases.
Concentrate the reaction to dryness and add more methanol and bring to reflux for 3
hours. Concentrate the reaction to dryness, then dissolve in dichloromethane and extract
with 1 N HC1 (2 X 150 mL). Make the acidic aqueous extracts basic using 50% NaOH
and Na2CO3. Treat the aqueous solution with dioxane (500 mL) and di-
tertbutylcarbonate (10.91 g, 50.00 mmol) for 3 days. Dilute the reaction with
dichloromethane, separate the layers and re-extract the aqueous with dichloromethane.
Wash the organic extracts with aqueous saturated sodium chloride, dry over MgSO4,
filter and concentrate to yield a crude oil. Chromatograph on silica utilizing (O®5®8 %
) ethyl acetate in dichloromethane to afford the title compound (4.20 g, 11.53 mmol).
MS(ES), m/z 307/309 (M+l minus t-butyl).
B. {2-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzenesulfonyl]-ethyl}-
carbamic acid tert-butyl ester
Use a procedure similar to Preparation 84B, where [2-(4-bromo-
benzenesulfonyl)-ethyl]-carbamic acid tert-butyl ester (4.10 g, 11.25 mmol) is converted
to the boronate ester (3.03 g, 7.36 mmol). MS(ES), m/z 353 (M+l minus t-butyl).
C. 2-(4- {7-[4-(2-Amino-ethanesulfonyl)-phenyl]-imida2o[l ,2-a]pyridin-3-yl} -phenyl)-N-
(5-tert-butyl-isoxazol-3-yl)-acetamide
Couple N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(7-chloro-imidazo[l,2-a]pyridin-3-yl)-
phenyl]-acetamide (0.700 g, 1.71 mmol) to {2-[4-(4,4,5,5-Tetramethyl-
[l,3,2]dioxaborolan-2-yl)-benzenesulfonyl]-ethyl}-carbamic acid tert-butyl ester (0.775
g, 1.88 mmol) using procedure similar to Example 115. Treat the crude extracts to SCX
ion exchange chromatography during which time some of the BOC-group is cleaved.
Elute from the SCX column and treat with 2N HC1 in dioxane (125 mL) and 10 mL of
methanol for 2 hours. Evaporate in vacuo to provide the intermediate (0.87 g, 1.38
mmol). MS(ES), m/z 616 (M+l).
D. N-(5-tert-Butyl-isoxazol-3-yl)-2-(4-{7-[4-(2-diethylamino-ethanesulfonyl)-phenyl]-
imidazo[ 1,2-a]pyridin-3-yl} -phenyl)acetamide

WO 2006/091671 PCT/US2006/006283
/2.2_
Combine 2-(4-{7-[4-(2-Amino-ethanesulfonyl)-phenyl]-imidazo[l,2-a]pyridin-3-
yl}-phenyl)-N-(5-tert-butyl-isoxazol-3-yl)-acetamide (0.87 g, 1.38 mmol) with acetic
acid (1 mL), methanol (20 mL) and acetaldehyde (0.152 g, 3.45 mmol) at ambient
temperature under nitrogen for 10 minutes. Add sodium cyanoborohydride at ambient
temperature. The reaction is complete within 3 hours. Evaporate under vacuum, re-
dissolved in methanol and dichloromethane and load onto an SCX column. Wash the
column with dichloromethane (50 mL) and methanol (50 mL) and elute with methanolic
ammonia. Chromatography on silica (0®2®4®5 %) methanol and dichloromethane
gives the title compound (21.0 mg). MS(ES), m/z 614 (M+l).
Example 210
3-{4-[7-(4-Methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-N-(3-
trifluoromethyl-phenyl)-propionamide

Combine 3-{4-[7-(4-methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-
phenyl}-propionic acid (132 mg, 0.314 mmol, 1.0 equiv) with anhydrous
dichloromethane (6.0 mL) in the presence of a catalytic amount of DMF (20 mL). Add
2.0 M oxalyl chloride in dichloromethane (235 mL, 1.5 equiv) via syringe over 30
seconds then stir for 18 hours at room temperature. Concentrate the reaction to dryness
under reduced pressure using a rotary evaporator.
Dissolve the crude acid chloride intermediate in anhydrous dichloromethane (3.0
mL) in the presence of DMAP (26.6 mg, 0.218 mmol, 0.3 equiv), 3-trifluoromethyl-
phenylamine (181 uL, 1.45 mmol, 2.0 equiv), and pyridine (235 mL, 2.90 mmol, 4.0
equiv) and allow to stir at room temperature for 24 hours. Apply the reaction mixture to
SCX resin (10 g), which is eluted with dichloromethane, methanol, then 2.0 M ammonia
in methanol. Concentrate the methanolic ammonia fraction to dryness under reduced
pressure using a rotary evaporator. Subject the residue to HPLC purification to give
133.0 mg of the title compound. MS (ES) m/z 564 (M+l).

WO 2006/091671 PCT/US2006/006283
12 3
Prepare the following according to procedures similar to Example 210:

Ex. Compound Name Physical DataMS(ES),(m/z)
211 N-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[7-(4-methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-propionamide 542 (M+l)
212 N-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[7-(4-methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-propionamide 556 (M+l)
213 3- {4- [7-(4-methanesulfonyl-phenyl)-imidazo [ 1,2-a]pyridin-3-yl]-phenyl} -N-(4-trifluoromethyl-phenyl)-propionamide 564 (M+l)
214 3- {3-[7-(4-methanesulfonyl-phenyl)-imidazo[ 1,2-a]pyridin-3-yl]-phenyl}-N-(3-trifluoromethyl-phenyl)-propionanxide 564 (M+l)
215 N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[7-(4-methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-propionamide 632 (M+l)
y Example 216
2-[4-(7-Pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyI-phenyl)-
thioacetamide

Add Lawesson's reagent (0.246 g, 0.61 mmol, 1.2 eq.) to the solution of 2-[4-(7-
pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-
acetamide (0.240 g, 0.51 mmol, 1.0 eq.) in hexamethylphosphoramide (2.5 mL). Stir the
reaction mixture at 80 °C overnight. Cool the mixture down to room temperature and
load onto a Varian MegaElut® SCX cartridge (5 gram cartridge prewashed with
methanol). Rinse with methanol to remove impurities then elute crude product with 2 M
NH3 in methanol. Concentrate this solution in vacuo then purify HPLC to give a yellow
foam (0.078 g, 31 %). MS (ES), m/z 489 (M+l).
Example 217

WO 2006/091671 PCT/US2006/006283

124
N-{4-[7-(4-Methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-benzyl}-2-(m-
trifluoromethyl-phenyl)-acetamide

A. N-[4-(7-Chloro-imidazo[l,2-a]pyridin-3-yl)-benzyl]-2-(m-trifluoromethyl-phenyl)-
acetamide
In a 40 mL septum capped vial purged with N2, add 4-(7-chloro-imidazo[l,2-
a]pyridin-3-yl)-benzylamine (125 mg, 0.48 mmol), magnetic stir bar, CH2Cl2(6 mL),
cool the vial in an ice bath and slowly add 1 mL (CH2Cl2 solution of m-trifluoromethyl-
phenylacetyl chloride, 0.48 mmol ). Add isopropyl ethyl amine (0.8 mL) with THF (2
mL). Remove the vial from the ice bath and heat to 40 °C for 6 hours. Add a trace of
MeOH and evaporate the solvents under vacuum and take up the oil into a minimal
amount of CH2C12 and chromatograph using SiO2 eluting with a gradient of 0.5 % to 5%
of 2 M NH3 in MeOH with the balance CH2Cl2. Isolate the product, dry in a vacuum
oven at 40 °C for 24 hours to give 144 mg (67 %) MS (ES), m/z 444 (M+l).
B. N-{4-[7-(4-Methanesulfonyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-benzyl}-2-(m-
trifluoromethyl-phenyl)-acetamide
In a 12 mL septum capped vial purged with N2 add N-[4-(7-chloro-imidazo[l,2-
a]pyridin-3-yl)-benzyl]-2-(m-trifluoromethyl-phenyl)-acetamide (144 mg, 0.32 mmol), 4-
(methylsulfonyl)phenyl boronic acid (89 mg, 0.44 mmols), 2-dicyclohexylphosphino-
2',6'-dimethoxy-l,r-biphenyl (23.6 mg) [X-Phos is alternatively used as the ligand in
this reaction], Pd(OAc)2 (6 mg), K3PO4 (218 mg, 1.02 mmol), 1,4-dioxane: H2O 2:1 (5
mL). Deoxygenate the vial again with N2 then heat to 45 °C for 24 hours. Cool the
reaction and transfer to a separatory funnel and discard the bottom aqueous layer.
Evaporate the solvents under vacuum and take up the residue into CH2Cl2 with a trace of
MeOH. Chromatograph the crude reaction on SiO2 eluting with a gradient of 0% to 8%
of 2 M NH3 in MeOH with the balance CH2C12 Dry the product in a vacuum oven at
40°C for 24 hours to give 38.6 mg (21%) MS (ES), m/z 564.3 (M+l).

WO 2006/091671 PCT/US2006/006283
125
Prepare the following according to procedures similar to Example 217:
Ex. Compound Name Physical DataMS(ES),(m/ z)
218 N-(5-tert-Butyl-thiazol-2-yl)-2- {2-fluoro-4-[7-(4-nitro-phenyl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-acetamide 530 (M+l)
Example 219
N-(4-tert-Butyl-pyridin-2-yl)-2-{2-fluoro-4-[7-(6-methyl-pyridin-2-yl)-imidazo[l,2-
a]pyridin-3-yl]-phenyl} -acetamide

In a stirred septum capped vial, charge 2-(4-bromo-2-fluoro-phenyl)-N-(4-tert-
butyl-pyridin-2-yl)-acetamide (400 mg, 1.09 mmol), 7-(6-methyl-pyridin-2-yl)-
imidazo[l,2-a]pyridine (228 mg, 1.09 mmol), KOAc (213 mg, 2.18 mmol), PdCl2(PPh3)2
and flushes with N2 needle for 15 minutes then one adds DMSO (5 mL) and de-
oxygenate with N2 needle and places vial in oil bath at 80 to 90 °C for 24 hours. Cool the
reaction then purify by passing through Varian SCX® (10 g) column that is pre-washed
with water and methanol, the product being eluted with (20%) 2 N NH3 in methanol/
(80%) DCM. Evaporate solvent from the product containing fractions under reduced
pressure. Chromatograph using (40g ISCO®) SiO2 eluting with a gradient of 0% to 10%
2 M NH3 in MeOH with the balance DCM. Evaporate solvents and purify by reverse
phase chromatography (C-18 acetonitrile/HzO with 0.1% TFA) Neutralize, extract, and
strip off solvents. Dry in vacuum oven to afford 118.4 mg (21.9 %) MS(ES), m/z 494
(M+l).

WO 2006/091671 PCT/US2006/006283

126
Prepare the following according to procedures similar to Example 219:

Ex. Name PhysicaldataMS(ES)m/z
220 N-(4-tert-Butyl-pyridin-2-yl)-2-{4-[7-(2-diethylaminomethyl-pyridin-4-yl)-imi dazo[ 1,2-a]pyridin-3-yl]-2-fluoro-phenyl} -acetamide 565(M+l)
221 N-(5-tert-Butyl-thiazol-2-yl)-2-{4-[7-(2-diethylaminomethyl-pyridin-4-yl)-imidazo[ 1,2-a]pyridm-3-yl]-2-fluoro-phenyl} -acetamide 571(M+l)
222 2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-N-(5-isopropyl-thiazol-2-yl)-acetamide 472(M+l)
223 N-(5-tert-Butyl-thiazol-2-yl)-2-{4-[7-(2-ethyl-pyridin-4-yl)-imidazo[l,2-a]pyridin-3-yl]-2-fluoro-phenyl}-acetamide 514(M+l)
224 N-(5-tert-Butyl-thiazol-2-yl)-2-{2-fluoro-4-[7-(2-morpholin-4-ylmethyl-pyridin-4-yl)-imidazo [ 1,2-a]pyri din-3 -y 1] -phenyl} -acetamide 585(M+l)
Example 225
2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(5-isopropyl-4-
methyl-thiazol-2-yl)-acetamide

Combine 7-pvridin-4-yl-imidazo[l,2-a]pyridine (0.242 g, 1.24 nunol), 2-(4-
Bromo-2-fluoro-phenyl)-N-(5-isopropyl-4-methyl-thiazol-2-yl)-acetamide (0.460 g, 1.24
mmol), and potassium acetate (0.243 g, 2.48 mmol) in DMSO (5 mL). De-gas the
mixture with N2 for 10 minutes, then add dichlorobis(triphenylphosphine) palladium(II)
(0.087 g, 0.124 mmol). Stir the reaction at 100°C under N2 for 14 hours. Purify using an
SCX cartridge (10 g VARIAN bond elut), eluting with 1:1 rnethanol:dichloromethane,
then 1:1 2 M NH3 in methanohdichloromethane. The latter is purified via reverse phase
chromatography using a 25 cm by 50.8 mm (i.d.) column w/10 micron particles
(MeCN/0.03%HCl H2O (5:95) to 100% MeCN; 30 minutes). Compound obtained is
extracted with ethyl acetate versus 1 N NaOH. The organic layer is washed with aqueous

WO 2006/091671 PCT/US2006/006283
127
aturated sodium chloride. Dry the resulting organics over magnesium sulfate, filter, and
concentrate to afford product (0.068 g, 11%). MS(ES), m/z 486 (M+l).
Prepare the following according to procedures similar to Example 219:

Ex. Name PhysicaldataMS(ES)m/z
226 N-(3-Acetyl-phenyl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phen-yl]-acetamide 465(M+l)
227 2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[5-(l-methyl-cyclopropyl)-[l,3,4]thiadiazol-2-yl]-acetamide 485(M+l)
228 N-(3-Dimethylaminomethyl-5-trifluoromethyl-phenyl)-2-[2-fluoro-4-(7-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide 548(M+l)
229 N-(3-tert-Butyl-5-morpholin-4-ylmethyl-phenyl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 578(M+l)
230 N-(3-tBrt-Butyl-5-dimethylaminomethyl-phenyl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazotl,2-a]pyridin-3-yl)-phenyl]-acetamide 536(M+l)
231 2-(2-Fluoro-4-{7-[2-(2-morpholin-4-yl-propyl)-pyridin-4-yl]-imidazo[l,2-a]pyridin-3-yl}-phenyl)-N-[5-(l-hydroxy-cyclobutyl)-thiazol-2-yl]-acetamide 627(M+l)
232 2-{2-Fluoro-4-[7-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-phenyl} -N-(4-trifluoromethyl-pyridin-2-yl)-acetamide 506(M+l)
233 N-(4-tert-Butyl-pyridin-2-yl)-2-{4-[7-(2,6-dimethyl-pyridin-4-yl)-imidazo[l,2-a]pyridin-3-yl]-2-fluoro-phenyl}-acetamide 508(M+l)
234 N-(5-tert-Butyl-thiazol-2-yl)-2-(2-fluoro-4-{7-[2-(2-pyrrolidin-l-yl-propyl)-pyridin-4-yl]-imidazo[l,2-a]pyridin-3-yl}-phenyl)-acetamide . 597(M+l)
235 N-(4-tert-Butyl-pyridin-2-yl)-2-(2-fluoro-4-{7-[2-(2-pyrrolidin-l- nyl-propyl)-pyridin-4-yl]-imidazo[ 1,2-a]pyridin-3-yl} -phenyl)-acetamide 591(M+l)
236 N-(5-tert-Butyl-[l,3,4]thiadiazol-2-yl)-2-(2-fluoro-4-{7-[2-(2-pyrrolidin- l-yl-propyl)-pyridin-4-yl]-imidazo[l ,2-a]pyridin-3-yI} -phenyl)-acetamide 598(M+l)
237 2-(2-Fluoro-4- {7-[6-(2-morpholin-4-yl-propyl)-pyridin-3-yl]-imidazo[l,2-a]pyridin-3-yl}-phenyl)-N-[(5-tert-Butyl)-[l,3»4]thiadiazol-2-yl]-acetamide 614(M+l)
238 N-(4-tert-Butyl-pyridin-2-yl)-2-(2-fluoro-4-{7-[6-(2-morpholin-4-yl-propyl)-pyridin-3-yl]-imidazo[l,2-a]pyridin-3-yl}-phenyl)-acetamide 607(M+l)

WO 2006/091671 PCMJS20O6/0O6283
128

239 N-(4-tert-Butyl-pyridin-2-yl)-2-(2-fluoro-4-{7-[6-(2-morpholin-4-yl-propyl)-pyridin-2-yl]-imidazo[l,2-a]pyridin-3-yl}-phenyl)acetamide 607(M+l)
240 2-(2-Fluoro-4- {7-[6-(2-morpholin-4-yl-propyl)-pyridin-2-yl]-imidazo[l,2-a]pyridin-3-yl}-phenyl)-N-[5-(l-hydroxy-cyclobutyl)-thiazol-2-yl]-acetamide 627(M+l)
241 3-(6-{ 2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetylamino}-2-methyl-4-trifluoromethyl-pyridin-3-yl)-N,N-dimethyl-acrylamide 603(M+l)
242 3-(4-tert-Butyl-6- {2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetylamino} -pyridin-3-yl)-N,N-dimethyl-acrylamide 577(M+l)
243 2-[2-Fluoro-4-(7-pyridin-2-yl-imidazo[l,2-Q]pyridin-3-yl)-phenyl]-N-(4-isobutyl-pyridin-2-yl)-acetamide 480(M+l)
244 N-(4-sec-Butyl-pyridin-2-yl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 480(M+l)
245 2- [2-Fluoro-4-(7-pyridin-4-yl-imidazo [ 1,2-a]pyridin-3-yl)-phenyl]-N-(4-isobutyl-pyridin-2-yl)-acetamide, hydrochloride salt 480(M+l)
246 N-(4-Cyclopropyl-pyridin-2-yl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a^pyridin-3-yl)-phenyl]-acetamide 464(M+l)
247 N-(3-tert-Butyl-phenyl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 479(M+l)
248 N-(4-Dimethylaminomethyl-pyridin-2-yl)-2-[2-fluoro-4-(7-2yridin-4-yl-imicIa2o[l,2-a]pyridin-3=yl)-phenyl]-acetamide 481(M+l)
249 2-[2-Fluoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-morpholin-4-ylmethyl-5-trifluoromethyl-phenyl)-acetamide 590(M+l)
250 2- [2-Fluoro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-N-(3-morpholin-4-ylmethyl-5-trifluoromethyl-pheTiyl)-acetamide 590(M+l)
251 3-{2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetylamino}-N-(tetrahydro-pyran-4-yl)-5-trifluoromethyl-benzamide 618(M+l)
252 2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2.-a]pyridin-3-yl)-phenyl]-N-[3-(morpholine-4-carbonyl)-5-trifluororaethyl-phenyl]-acetamide, hydrochloride salt 604(M+l)
253 N-[5-tert-Butyl-4-(2-dimethylamino-ethoxy)-2-methyl-phenyl]-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 580(M+l)
254 N-(5-tert-Butyl-thiazol-2-yl)-2-[4-(7-pyridin-4-yl-imldazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 468(M+l)
255 N-(5-tert-Butyl-[l,3,4]thiadiazol-2-yl)-2-[2-chloro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide 503(M+l)
256 N-(5-tert-Butyl-thiazol-2-yl)-2-[2-chloro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide 502(M+l)

WO 2006/091671 . PCT/US2006/006283
129

257 N-(4-tert-Butyl-pyridin-2-yl)-2-[2-chloro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yI)-phenyl]-acetamide 496(M+l)
258 2-[2-Nitro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(4-trifluoromethyl-pyridin-2-yl)-acetamide 519(M+l)
259 N-(4-tert-Butyl-pyridin-2-yl)-2-[4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 462(M+l)
260 N-(4-tert-Butyl-pyridin-2-yl)-2-[4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 462(M+l)
261 N-(4-tert-Butyl-6-dimethylaminomethyl-pyridin-2-yl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 537(M+l)
262 N-(4-tert-Butyl-6-dimethylaminomethyl-pyridin-2-yl)-2-[2-fluoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 537(M+l)
Example 263
N-(4-tert-butyl-6-moq)holin-4-ylmethyl-pyridin-2-yl)-2-[2-fluoro-4-(7-pyridin-4-yl-
imidazo[l,2-a]pvridin-3-yl)-phenyl]-acetarnide

a]pyridin-3-yl)-phenyl]-acetic acid dihydrochloride (6.24 g, 14.84 mmol) and 4-tert-
butyl-6-morpholin-4-ylmethyl-pyridin-2-ylamine (3.70 g, 14.84 mmol) in anhydrous
DMF (40 mL). Add diisopropyl-ethylamine (8.5 mL, 48.97 mmol) and HATU (6.21 g,
16.32 mmol). Stir the reaction mixture at room temperature for 40 minutes. Dilute with
ethyl acetate (800 mL). Wash with aqueous saturated sodium chloride (3 x 100 mL),
sodium bicarbonate (sat. 3 x 100 mL), water (3 x 100 mL). Dry the organic layer over
magnesium sulfate, filter off the drying reagent, and concentrate to oil. Chromatograph
the crude product on silica (0-4% 2 M ammonia methanol/dichloro-rnethane).
Recrystallize from dichloromethane/ether/hexane to provide the title compound 5.50 g
(9.5 mmol, 64%) white solid as product. MS (ES), m/z 579 (M+l).

WO 2006/091671 PCT/US2006/006283
130
Prepare the following according to procedures similar to Example 219:
Ex. Name PhysicaldataMS(ES)m/z
264 N-(4-tert-Butyl-6-morpholin-4-ylmethyl-pyridin-2-yl)-2-[2-fluoro-4-(7-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide 579(M+l)
265 N-(4-tert-Butyl-6-pyrrolidin-l-ylmethyl-pyridin-2-yl)-2-[2-fluoro-4-(7-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide 563(M+l)
266 N-(4-tert-Butyl-pyridin-2-yl)-2-[2-methyl-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 476(M+l)
267 N-(4-tert-Butyl-pyridin-2-yl)-2-[2-methyl-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 476(M+l)
268 N-(4-tert-Butyl-6-morpholin-4-ylmethyl-pyridin-2-yl)-2- {2-fluoro-4-[7-(2-methyl-pyridin-4-yl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-acetamide 593(M+l)
269 N-(5-Cyclobutyl-thiazol-2-yl)-2-(2-fluoro-4-{7-[2-(2-morpholin-4-yl -propyl)-pyridin-4-yl] -imidazo [1,2-a]pyridin-3-yl} -phenyl)-acetamide 611(M+l)
270 N-(5-Cyclobutyl-thrazol-2-yl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide 484(M+l)
271 2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(5-isopropyl-4-pyrrolidin-l-ylmethyl-thiazol-2-yl)-acetamide 555(M+l)
272 N-(5-Cyclopropyl-[l,3,4]thiadiazol-2-yl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl] –acetamide 471(M+l)
273 N-(5-tert-Butyl-thiazol-2-yl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide 486(M+l)
274 N-(5-tert-Butyl-[l,3,4]thiadiazol-2-yl)-2-[2-fluoro-4-(7-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide 487(M+l)
Example 275
iV-(5-rerr-Butyl-[l,3.4]thiadiazol-2-yl-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[l,2-
aJpyridm-3-yl)-phenyl]-acetamide

Dissolve 2-(4-bromo-2-fluoro-phenyl)- N-(5-ter-butyl -[l,3,4]thiadiazol-2-yl)-
acetamide (0.86 g, 2.31 mmol) and 7-pyridin-4-yl-imidazo[l,2-a]pyridine (0.45 g, 2.31
mmol) in dimethyl sulfoxide (2.5 mL). Add potassium acetate (0.46 g, 4.62 mmol), and

WO 2006/091671 PCT/US2006/006283
131
trans-dichloro bis(triphenylphosphine) palladium (II) (0.16 g, 0.23 mmol), deoxygenate
and fill with nitrogen (2x). Stir the reaction mixture over night at 100 °C under nitrogen.
Add ice water (16 mL), filter off the solid and purify via flash silica gel chromatography
(0-5% methanol/dichloromethane) to afford 0.72 g (1.48 mmol, 64%) of yellow solid as
the title compound. MS (ES), m/z 487.0 (M+l).
Prepare the following according to procedures similar to Example 219:

Ex. Name PhysicaldataMS(ES)m/z
276 2-[2-Fluoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-pyrrolidin-l-ylmethyl-5-trifluoromethyl-phenyl)-acetamide 574(M+l)
277 2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-N-(3-pyrrolidin-l-ylmethyl-5-trifluoromethyl-phenyl)-acetamide 574(M+l)
278 N-(4-tert-Butyl-pyridin-2-yl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide 480(M+l)
279 N-(4-tert-Butyl-pyridin-2-yl)-2-[2-fluoro-4-(7-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-acetamide 480(M+l)
280 2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[5-(l-hydroxy-l-methyl-ethyl)-thiazol-2-yl]-acetamide 488(M+l)
281 N-(5-tert-Butyl-thiazol-2-yl)-2-{2-fluoro^-[7-(2-methyl-p yri din-4-yl)-imidaz6[ 1,2-a]pyridin-3-yl]-phenyl} -acetamide 500(M+l)
282 2-{ 2-Fluoro-4-[7-(2-methyl-pyridin-4-yl)-imidazo[l ,2-a]pyridin-3-yl]-phenyl} -N-(4-trifluoromethyl-pyridin-2-yl)-acetamide 506(M+l)
283 N-(4-tert-Butyl-pyridin-2-yl)-2-{2-fluoro-4-[7-(2-methyl-pyridm-4-yl)-irmd^o[l,2-a]pyridin-3-yl]-phenyl} -acetamide 494(M+l)
284 2-{ 2-Fluoro-4-[7-(2-methyl-pyridin-4-yl)-imidazo[ 1,2-a]pyridin-3-yl]-phenyl}-N-[5-(l-hydroxy-l-methyl-ethyl)-thiazol-2-yl]-acetamide 502(M+l)
285 2-[2-Fluoro-4-(7-pyridin-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-phenyl]-N-[5-(l-hydroxy-l-methyl-ethyl)-thiazol-2-yl]-acetamide 488(M+l)
286 2-[2-Fluoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[5-(l-hydroxy-cyclobutyl)-thiazol-2-yl]-acetamide 500(M+l)
287 2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[5-(l-hydroxy-cyclobutyl)-thiazol-2-yl]-acetamide 500(M+l)

WO 2006/091671 PCT/US2006/006283
132.

288 2-{2-Fluoro-4-[7-(2-methyl-pyridin-4-yl)-imidazo[ 1,2-a] pyri din-3 -yl] -phenyl} -N-[5-( 1 -h ydroxy-cyclobutyl)-thi azol-2-yl]-acetamide 514(M+l)
289 N-(6-tert-Butyl-pyrimidin-4-yl)-2-[4-(7-pyridin-4-yl-imidazo [ 1,2-a] pyridin-3 -yl)-phenyl]-acetamide 463(M+l)
291 N-(6-Methyl-4-trifluoromethyl-pyridin-2-yl)-2-[4-(7-pyridin-4-yl-imidazo [ 1,2a]pyri di n-3-yl)-phenyl]-acetamide 488(M+l).
Example 292
2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(5-isopropenyl-
thiazol-2-yl)-acetamide

Isolate during the preparation of the Example 2-[2-Fluoro-4-(7-pyridin-4-yl-
imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[5-(l-hydroxy-l-methyl-ethyl)-thiazol-2-yl]-
acetamide. MS (ES), m/z 470 (M+l).
Isolate the following similarly from the corresponding carbinol syntheses:

Ex. Name PhysicalDataMS(ES),(m/z)
293 2-[2-Fluoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(5-isopropenyl-thiazol-2-yl)-acetamide 470(M+l)
294 2- {2-Fluoro-4-[7-(2-methyl-pyridin-4-yl)-imidazo [ 1,2-a]pyridin-3-yl]-phenyl} -N-(5-isopropenyl-thiazol-2-yl)-acetamide 482(M+l)
Example 295 and 296
(R)-and(S)-N-(4-tert-Butyl-pyridin-2-yl)-2-(2-fluoro-4-{7-[2-(2-morpholin-4-yl-
propyl)-pyridin-4-yl]-imidazo[l,2-a]pyridin-3-yl}-phenyl)-acetamide

WO 2006/091671 PCT/US2006/006283
133

Prepare racemate with procedures similar to Example 219 and separate into
enantiomers by chiral HPLC (Column: .46 xl5 cm Chiralcel OD-H, Eluent: 100% 3A
ethanol w/ 0.2% DMEA, Flow: 0.6 mL/min, TJV: 260 ran) both enantiomers at
approximately 99% ee as characterized by chiral LC. Enantiomer A: MS(ES), m/z 607
(M+l); enantiomer B: MS(ES), m/z 607 (M+l).
Examples 297 and 298
(R)- and (S)-24561102-(2-Ruoro-4-{7-[2-(2-morpholin-4-yl-propyl)-pyridin-4-yl]-
imidazo[l,2-a]pyridin-3-yl}-phenyl)-N-(4-trifluoromethyl-pyridin-2-yl)-acetamide

Combine 7-[2-(2-morpholin-4-yl-propyl)-pyridin-4-yl]-imidazo[l ,2-a]pyridine
(1.0 g, 3.1 mmol), 2-(4-bromo-2-fluoro-phenyl)-N-(4-trifluoromethyl-pyridin-2-yl)-
acetamide (1.29 g, 1.1 equiv.), potassium acetate (0.61 g, 2 equiv.), and DMSO (5 mL) in
a RBF. Degas thouroughly with nitrogen then add dichloro-bis(triphenylphosphine)
palladium (II) (0.22 g, 10 mol%) and heat the reaction overnight at 90 °C. Dilute with
ethyl acetate and 1N NaOH (aq). Extract organics with water, 1N NaOH (aq), and brine.
Dry organics over magnesium sulfate, filter and concentrate to dryness. Purify by reverse
phase (25% MeCN : 0.03% HC1 in water ® 100% MeCN, C18 column). Material
impure after chromatography. Combine all fractions containing product. Dilute with
ethyl acetate then wash with 1 N NaOH followed by brine. Dry organics over
magnesium sulfate, filter and concentrate to give impure freebase (1.17 g). Purify on
silica gel (3% MeOH: DCM ® 6% MeOH: DCM ® 10% MeOH: DCM® 10% 2 M
NH3 in MeOH : DCM) to give a light yellow solid (0.977g). Dry overnight at 60 °C in a

WO 2006/091671 PCT/US2006/006283
134

vacuum oven. A second silica column (3% MeOH: DCM ® 6% MeOH : DCM ®
10% MeOH: DCM) provides clean product (0.656 g). Dry overnight at 60 °C in a
vacuum oven to give 0.57 g product (30%). LCMS (ES), m/z 619 (M+l). Separation of
enantiomers by chiral HPLC (Column: .46x15 cm Chiralcel OD-H, Eluent: 100% 3A
ethanol w/ 0.2% DMEA, Flow: 0.6 ml/min, UV: 260 nm) provided both enantiomers at
approximately 99% ee as characterized by chiral LC. Ex 297, Isomer 1 - 7.3 minutes.
Ex 298, Isomer 2-8.8 minutes. Note : absolute stereochemistry not determined.
Example 299 and 300
(R)- and (S)-N -(5-tert-Butyl-thiazol-2-yl)-2-(2-fluoro-4-{7-[2-(2-morpholin-4-yl-
propyl)-pyridin-4-yl]-imidazo[ 1,2-a]pyridin-3-yl} -phenyl)-acetamide

Prepare racemate with procedures similar to Example 219 and separate into
enantiomers by chiral HPLC (Column: .46x15 cm Chiralcel OD-H, Eluent: 100% 3A
ethanol w/ 0.2% DMEA, Flow: 0.6 mL/min, UV: 260 nm) both enantiomers at
approximately 99% ee as characterized by chiral LC. MS(ES), m/z 613.3 (M+l).
Example 301 and 302
(R)-and(S)-2-(2-Fluoro-4-{7-[2-(2-morpholin-4-yl-propyl)-pyridin-4-yl]-imidazo[l,2-
a]pyridin-3-yl} -phenyl)-N-[5-( l-methyl-cyclopropyl)-[ 1,3,4]thiadiazol-2-yl]-acetamide


WO 2006/091671 PCT/US2006/006283
135
Prepare racemate with procedures similar to Example 219 and separate into
enantiomers by chiral HPLC (Column: .46x15 cm Chiralcel OD-H, Eluent: 100% 3A
ethanol w/ 0.2% DMEA, Flow: 0.6 mL/rnin, UV: 260 nm) both enantiomers at
approximately 99% ee as characterized by chiral LC. MS(ES), m/z 612.0 (M+l).
Example 303
N-(5-tert-Butyl-isoxazol-3-yl)-2-{4-t7-(lH-pyrazol-4-yl)-imidazo[l,2-a]pyridin-3-yl]-
phenyl}-acetamide

A. N-(5-tert-Butyl-isoxazol-3-yl)-2-{4-[7-(l-dimethylsulfamoyl- lH-pyrazol-4-yl)-
imidazo[l,2-a]pyridin-3-yl]-phenyl}-acetamide
Prepare with procedures similar to Example 219. MS (ES), m/z 548 (M+l).
B. N-(54ert-Butyl4soxazol-3-yl)-2-{4-[7-(1H-pyrazol-4-yl)-irnidazo[l,2-a]pyridin-3-
yl]-phenyl }-acetamide
Dissolve N-(5-tert-Butyl-isoxazol-3-yl)-2-{4-[7-(l-dimethylsulfamoyl-lH-
pyrazol-4-yl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-acetamide in CH2Cl2 methanol and 1
N HC1 in ether in equal volumes and then concentrate to give a solid. Dissolve the solid
in HO Ac and stir for 1 hour. Concentrate and purify by silica gel chromatography with
0-5 % MeOH in CH2C12. MS(ES), m/z 441 (M+l).
The following example is prepared with a procedure similar to Example 303:

Ex. Name PhysicalDataMS(ES),(m/z)
304 N-(5-tert-Butyl-thiazol-2-yl)-2-{4-[7-(lH-pyrazol-4-yl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-acetamide 457(M+l)

WO 2006/091671 PCT/US2006/006283
136
Example 305
2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[5-(tetrahydro-
pyran-4-yl)-thiazol-2-yl]-acetamide

A. 2-[2-fluoro-4-yl-imidazo[l,2-a]pyridine-3-yl)-phenyl]-N-[5-(4-hydroxy-tetrahydro-
pyran-4-yl)-thiazol-2-yl]-acetamide
The title compound is prepared with procedures similar to Example 219. MS
(ES), m/z53O(M+l).
B. 2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a3pyridin-3-yl)-phenyl]-N-[5-(tetrahydro-
pyran-4-yl)-thiazol-2-yl]-acetamide
Dissolve compound 2-[2-fluoro-4-yl-imidazo[l,2-a]pyridine-3-yI)-phenyl]-N-[5-
(4-hydroxy-tetrahydro-pyran-4-yl)-thiazol-2-yl]-acetamide (0.186 g, 0.35 mmol, 1.0 eq.)
in trifluoroacetic acid (8 mL). Add Pearlman's catalyst (0.12 g) to the mixture. Stir the
reaction mixture in hydrogen atmosphere (50 psi) for over night. Concentrate in vacuo.
Purify by column chromatography (0%® 5% 2 M ammonia methanol in
dichloromethane) to afford the title product (1.38 g, 46%). MS(ES), m/z 514 (M+l).
The following example is prepared with procedures similar to Example 305:

Ex. Name PhysicalDataMS(ES),(m/z)
306 2-[2-Ruoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[5-(tetrahydro-pyran-4-yl)-thiazol-2-yl]-acetamide 514(M+l)
Example 307
N-[4-Dimethylaminomethyl-5-(l-methyl-cyclopropyl)-thiazol-2-yl]-2-[2-fluoro-4-(7-
pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide

WO 2006/091671 PCT/US2006/006283
137

Combine 2-(4-bromo-2-fluoro-phenyl)-N-[4-dimethylaminomethyl-5-( 1 -methyl-
cyclopropyl)-thiazol-2-yl]-acetamide (0.45 g, 1.06 mmol), 7-pyridin-4-yl-irnidazo[l,2-
a]pyridine (0.206 g, 1 equiv.), potassium acetate (0.52 g, 5 equiv.), tetrabutylammonium
bromide (0.34 g, 1 equiv.), tris(2,4-di-t-butylphenyl)phosphite (0.034 g, 5 mol%) and
NMP (10 mL). De-gas with nitrogen then add palladium (II) acetate (0.012 g, 5 mol %)
and place under nitrogen. Heat at 120 °C for 24 hours then let stir at room temperature
for an additional day. Dilute with ethyl acetate then wash with water, 1 N NaOH (aq),
and aqueous saturated sodium chloride. Dry organics over MgSO4, then filter and
concentrate. Purify by reverse phase C18 column HPLC employing a gradient of 5 to
65% to 100% acetonitrile versus 0.03% aqueous HC1 then freebase by extraction with
ethyl acetate versus 1 N NaOH (aq). Dry the organics over MgSO4, then filter, and
concentrate to give product (118 mg tan solid, 21%). MS (ES), ni/z 541 (M+l).
The following compound is prepared with procedures similar to Example 307:

Ex. Name PhysicaldataMS(ES)m/z
308 N-[3-(2,2-Dimethyl-propionyl)-phenyl]-2-[2-fluoro-4-(7-pyridin-4-yl-irnidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide 507(M+l)
Example 309
N-[4-Dimethylaminomethyl-5-(l-methyl-cycloprppyl)-thiazol-2-yl]-2-[2-fluoro-4-(7-
pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetamide


WO 2006/091671 PCT/US2006/006283
138

Combine [2-fluoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetic
acid, dihydrochloride (0.190 g, 0.452 mmol) and 4-Dimethylaminomethyl-5-(l-methyl-
cyclopropyl)-thiazol-2-ylamine (0.105 g, 0.497 mmol) in DMF (4 mL). Add N,N-
diisopropylethylamine (0.26 mL, 1.49 mmol), then 0-(7-azabenzotriazol-l-yl)-
N,N,N\N'-tetramethyluronium hexafluorophosphate (0.190 g, 0.500 mmol). The
reaction mixture is stirred for 14 hours under N2. Purify using an SCX cartridge (10 g
VARIAN BondElut®), eluting with 1:1 methanol:dichloromethane, then 1:1 2 M NH3 in
methanohdichloromethane. Purify via reverse phase chromatography using a 25 cm by
50.8 mm (i.d.) column w/10 micron particles (MeCN/0.03%HCl H2O (5:95) to 100%
MeCN; 30 min). Partition between ethyl acetate and 1 N NaOH. Wash the organic layer
with aqueous saturated sodium chloride, dry over magnesium sulfate, filter, and
concentrate to the title compound (0.054 g, 22%). MS(ES), m/z 541 (M+l).
Prepare the following according to procedures similar to Example 309:

Ex. Name PhysicaldatatMS(ES)m/z
310 2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide 484 (M+l)
311 2-[2-Fluoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[5-(l-methyl-cyclopropyl)-4-morpholin-4-ylmethyl-thi azol-2-yl] -acetami de 583 (M+l)
312 2-[2-Fluoro-4-(7-pyridin-4-yl-irnidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[5-(l-methyl-cyclopropyI)-4-morpholin-4-ylmethyl-thiazol-2-yl]-acetamide 583 (M+l)
313 2-[2-Huoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[4-(dimethylamino-methyl)-5-tert-butyl-thiazol-2-yl]-acetamide 543 (M+l)
314 2-[2-Fluoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[4-(dimethylamino-methyl)-5-tert-butyl-thiazol-2-yl]-acetamide 543 (M+l)
Example 315
2-[2-Fluoro-4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-[5-tert-butyl-4-
morpholin-4-ylmethyl-thiazol-2-yl]-acetamide

WO 2006/091671 PCT/US2006/006283

Combine [2-fluoro-4-(7-pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-acetic
acid, dihydrochloride (0.500 g, 1.19 mmol) and 5-tert-Butyl-4-morpholin-4-ylmethyl-
thiazol-2-ylamine (0.334 g, 1.31 mmol) in DMF (6 mL). Add N,N-diisopropyl-
ethylamine (0.54 mL, 3.93 mmol), then O-(7-azabenzotriazol-l-yl)-N,N,N N'-tetra- .
methyluronium hexafluorophosphate (0.498 g, 1.31 mmol). The reaction mixture is
stirred over the weekend under N2. Purify using an SCX cartridge (10 g VARIAN
BondElut®), eluting with 1:1 methanol:dichloromethane, then 1:1 2 M NH3 in
methanoV.dichloromethane. Concentrate the latter and purify via reverse phase
chromatography using a 25 cm by 50.8 mm (i.d.) column w/10 micron particles
(MeCN/0.03%HCl H2O (5:95) to 100% MeCN; 30 min). Partition between ethyl acetate
and 1 N NaOH. Dry the organic layer over magnesium sulfate, filter, and concentrate to
the title compound (0.190 g, 27%). MS(ES), m/z 585 (M+l).
Prepare the following according to procedures similar to Example 309:

Ex. Name PhysicaldatatMS(ES)m/z
316 2- [2-Fluoro-4- (7-pyridin-2-yl-imidazo [ 1,2-a]pyridin-3-yl)-phenyl]-N-[5-tert-butyl-4-morpholin-4-ylmethyl-thiazol-2-yl]-acetamide 585 (M+l)
Example 317
2-{4-[7-(l-Oxy-pyridin-4-yl)-imidazo[l,2-a]pyridin-3-yl]-phenyl}-N-(3-
trifluoromethyl-phenyl)-acetamide


WO 2006/091671 PCT/US2006/006283
140

Dissolve 2-[4-(7-pyridin-4-yl-imidazo[l,2-a]pyridin-3-yl)-phenyl]-N-(3-
trifluoromethyl-phenyl)-acetamide (0.80 g, 1.69 mmol) in 6 mL dichloromethane, add
MTO (about 2 mg, 8.5micromol, 0.005 eq), stir to dissolve, then add 2 mL water and
0.245 mL of 30% aqueous hydrogen peroxide to give a heavy yellow slurry. Stir 16-24
houtd at room temperature, add additonal MTO (about 2 mg) and hydrogen peroxide
(0.245 mL), stir 24 hours at room temperature. Finally, add another 2 mg MTO and 0.50
mL of hydrogen peroxide solution, stir 16 hours at room temperature. Remove solvents
using a rotoraevaporator to afford a yellow solid. Dissolve the solid in dichloromethane-
methanol, apply to a 120 g silica cartridge and elute with a gradient of 0-->10% methanol
in dichloromethane over 5 minutes. When unreacted starting acetamide has eluted, re-
equilibrate the cartridge with 500 mL dichloromethane and elute with a gradient of 0—
>10% 1 N NH3-methanol in dichloromethane over 30 minutes. Pool and concentrate
clean fractions to give a yellow brittle foam and yellow glass. Resuspend the glass and
foam in diethyl ether, remove solvents in vacuo, then dry at 50 °C under high vacuum to
afford 330 mg (40%) of the title compound as a crystalline yellow solid. LCMS (ES) m/z
489 (M+l), 487 (M-).
Example 318
1 -(4- {7-[4-(4-Methyl-piperazine- l-carbonyl)-phenyl] -imidazo[ 1,2-a]pyridin-3-yl} -
benzyl)-3-(3-trifluoromethyl-phenyl)-urea

Combine {4-[3-(4-aminomethyl-phenyl)-imidazo[l,2-a]pyridin-7-yl]-
phenyl}-(4-methyl-piperazin-l-yl)-methanone, bis hydrochloride (0.30 g, 0.56
mmol), 3-trifluoromethylphenyl isocyanate (0.1 mL, 0.73 mmol) and triethylamine
(0.4 mL, 2.9 mmol) in DMSO (10 mL). Filter the solution through 10 g SCX column
eluting with methanol ® 2 N ammonia in methanol. Concentrate fractions containing
product to give a residue. Purify by chromatography (5% methanol in

WO 2006/091671 PCT/US2006/006283
141
dichloromethane®10% methanol in dichloromethane® 10% 2 N ammonia methanol
in dichloromethane) to afford product (0.18 g, 52%). MS(ES), m/z 613 (M+l).
Example 319
l-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[4-(4-methyl-piperazine-l-carbonyl)-phenyl]-
imidazo[ 1,2-a]pyridin-3-yl} -benzyl)-urea

Combine {4-[3-(4-aminomethyl-phenyl)-imidazo[l,2-a]pyridin-7-yl]-
phenyl}-(4-methyl-piperazin-l-yl)-methanone, bis hydrochloride (0.30 g, 0.56
mmol), (5-tert-butyl-isoxazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (0.2 g,
0.63 mmol) and triethylamine (0.4 mL, 2.9 mmol) in DMSO (10 mL). Heat the
mixture to 70 °C, stir five hours, and cool to room temperature.' Filter the solution
through 10 g SCX column eluting with methanol ® 2 N ammonia in methanol.
Concentrate fractions containing product to give a residue. Purify by chromatography
(5% methanol in dichloromethane ® 10% methanol in dichloromethane® 10% 2 N
ammonia methanol in dichloromethane) to afford product (0.048 g, 15%). MS(ES),
m/z 592 (M+l).
Example 320
1 -(5 -tert-B utyl-isoxazol -3-yl)-3-(2-fluoro-4- {7-[4-(piperazine-1 -carbonyl)-phenyl] -
imidazo[ 1,2-a]pyridin-3-yl} -phenyl)-urea hydrochloride

Dissolve 4-[4-(3-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-3-fluoro-phenyl}-
imidazo[l,2-a]pyridin-7-yl)-benzoyl]-piperazine-l-carboxylic acid tert-butyl ester (1.53
g, 2.24 mmol) in CH2C12 (25 mL), to which is added HC1 (5.6 mL, 4 M in dioxane). Stir

WO 2006/091671 PCT/US2006/006283
142-
at room temperature for three hours, then concentrate in vacuo to give light brown solid
as product (1.60 g, 115%). MS (ES), m/z 582 (M+l, free base).
The compounds of the present invention are preferable formulated as
pharmaceutical compositions administered by a variety of routes. Most preferably,
such compositions are for oral administration. Such pharmaceutical compositions
and processes for preparing same are well known in the art. See, e.g., REMINGTON:
THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al., eds., 19th
ed., Mack Publishing Co., 1995).
The compounds of Formula I are generally effective over a wide dosage
range. For example, dosages per day normally fall within the range of about 0.1 to
about 500 mg/kg of body weight. In some instances dosage levels below the lower
limit of the aforesaid range may be more than adequate, while in other cases still
larger doses may be employed without causing any harmful side effect, and therefore
the above dosage range is not intended to limit the scope of the invention in any way.
It will be understood that the amount of the compound actually administered will be
determined by a physician, in the light of the relevant circumstances, including the
condition to be treated, the chosen route of administration, the actual compound or
compounds administered, the age, weight, and response of the individual patient, and
the severity of the patient's symptoms.
The following assay is performed to measure the IC50 values of inhibition of
phosphorylation of VEGF-R2 with compounds of the present invention.
Autophosphorylation enzyme assay
A. VEGFR2 (KDR) cloning and purification.
The isolated catalytic domain (Amino Acids 807-1356) of VEGFR2 (KDR-CD,
cloned from a human heart cDNA library) is cloned by standard PCR procedures (pCR-
Script to make plasmid P34O) as a BamHI/HindIII fragment using the following primers:
Upper: 5'-CCATGGATCCAGATGAACTCCC-3' and Lower: 5'-
GAAGCTTAAACAGGAGGAGAGCTCAG-3', its nucleotide sequence is verified and it
is subcloned into the pFASTBac-HIS™ vector system (Gibco-BRL) (to give plasmid

WO 2006/091673 PCT/US2006/006283
143
B344) for baculovirus expression. (Carroll, et al., J. Biol. Chem, 268,12837-42 (1993).
KDR-CD is expressed as an N-terminal 6XHIS fusion protein in Sf9 cells (Gibco-BRL)
and purified according to standard affinity chromatography protocols (For example,
Amersham Pharmacia Biotech: Affinity Chromatography Principles and Methods #18-
1022-29). Briefly, 15-25 g pellets are lysed in lysis buffer (50 mM Tris pH 7.5, 150 mM
NaCl, 0.5% NP40 (CalbioChem) with freshly added 20 mM -mercaptoethanol, 10 mM
imidazole, 1 mM PMSF(protease inhibitor (phenylmethanesulfonyl fluoride) from
Sigma), 1X EDTA-free complete protease inhibitor (Boehringer Mannheim)) on ice for
30 minutes. The cell lysates are cleared by centrifugation at 30,000 g for 20 minutes at 4
C, filtered through a 0.2 M filter and applied to a NiNTA column (Qiagen). Unbound
protein is removed with successive RIPA buffer washes (50 mM Tris pH 7.5, 150 mM
NaCl; 1% NP40, 1 mM EDTA, 0.25% sodium deoxycholate, 20 mM -mercaptoethanol),
lysis buffer washes and finally IX kinase buffer (KB) washes (100 mM HEPES pH 7.5,
10 mM MnCk, 5 mM -mercaptoethanol). KDR protein is eluted in IX KB containing a
linear gradient of 200 mM imidazole over 10 column volumes. The peak fractions (based
on a SDS-PAGE gel analysis) are combined, concentrated by CentriconTM to -1 mg/mL
and desalted over an HR26/10 desalting column (Amersham Pharmacia) in 1X KB. This
KDR prep is estimated to be -40% pure with only KDR tyrosine kinase activity
detectable by anti-phosphotyrosine western analysis following the in vitro
autophosphorylation reaction.
B. KDR-CD In Vitro Autophosphorylation Kinase Assay.
Kinase reactions contain 1 mg total protein in 40 mL reaction volume containing
4% (v/v) DMSO final concentration, 1 mM ATP, 1 uCi/rxn 33P-ATP (fromNEN) in 1X
KB. A compound dilution series of 20 mM to 1.0 nM is added to the above reaction to
determine compound activity; test compound may be pre-incubated with KDR enzyme
for up to 30 minutes at 30 °C prior to addition of the radiolabel. The radiolabeling
reaction is carried out at 30 °C for 20 minutes before adding 100 mL 25%TCA with 3 mM
ATP to stop the reaction, then precipitated with 50 mL 1 mg/mL BSA. The quenched
reactions are transferred to MultiScreenTM-FC plates (Millipore) and incubated for

WO 2006/091671 PCT/US2006/006283
144

1 hour at room temperature. The plates are filtered, washed 3X with 250 mL 10% TCA
and blotted dry. MicroScintTM20 (Packard) is added and the plate is counted on a Wallac
MicrobetaTM Dougher-Vermazen, M. et al., Biochem Biophys Res Commun 205(1):
728-738 (1994). The IC50 values are calculated from a logistic 4-parameter curve fit. For
all examples included herein, the IC50 values are less than 1.0 x 10-6 M.
All values are determined using a 30 minute preincubation of compound and •
enzyme prior to initiating the labeling reaction and represent the average of at least two
separate determinations:
Example IC50 (nM)
39 28
130 42
173 26
196 106
289 41
303 46
In Vivo Efficacy in PC-3 Prostate Tumor Xenografts
Male SCID mice (Fox Chase, Taconic laboratories) are implanted s.c. in the rear
flank with 0.2 mL of a cell suspension prepared in serum-free media containing 5 x 106
PC-3 human prostate adenocarcinoma cells (obtained from ATCC). Example 130 is
prepared as a suspension in l%CMC/.25% Tween 80 and administered by oral gavage for
21 days beginning after tumors reach approximately 150-200 mg (volume calculated by I
x w2 x 0.536 where l is the larger and w is the smaller of perpendicular diameters
determined by caliper measurement). Example 130 is administered twice daily (12 hours
apart) for the 15, 7.5, and 3.75 mg/kg doses while the 30 mg/kg dose is given once daily.
Groups consists of 8 mice each and one group receives 0.2 mL of the CMC/Tween
vehicle twice daily as a control. Statistical analysis is performed by two-way ANOVA
and all treatment groups are statistically different from the control group (p < 0.001) at
study termination:
Mean Tumor Volumes and Std Errors
1%CMC/.25%PS8O, Ex 130, 3.75

WO 2006/091671 PCT/US2006/006283
145-
0.2 mL mg/kg
Day n Mean SE Signif. n Mean SE Signif.
55 8 715.3 123.3 Ctrl 8 268.1 36.5 **
57 8 880.6 153.4 Ctrl 8 310.1 36.8 ***
Ex 130,15
Ex 130,7.5 mg/kg mg/kg
Mean
55 8 100.8 21.1 *** 6 67.7 16.9 ***
5? 8 86.3 19 *** 6 62.2 17.4 ***
Ex 130, 30 mg/kg
SE = Std Error
-55 8 95.7 16.6 *** ***: p<= 0.001
57 8 86.8 17 *** **: 0.001