SUBSTITUTED IMIDAZO[1,2B]PYRIDAZINES AS KINASE INHIBITORS, THEIR PREPARATION AND USE AS MEDICAMENTS

IMIDAZO[1,2B]PYRIDAZINES SUBSTITUEES CONSTITUANT DES INHIBITEURS DE KINASES, LEUR PRODUCTION ET LEUR UTILISATION COMME MEDICAMENTS

English Abstract

The invention relates to novel inhibitors of kinases, methods for preparing
such
inhibitors, intermediates for the preparation of such inhibitors and uses of
such
inhibitors.

French Abstract

L'invention concerne de nouveaux inhibiteurs de kinases, des procédés de production de ces inhibiteurs, des produits intermédiaires pour produire ces inhibiteurs et des utilisations de ces inhibiteurs.

Claims

-176-
The embodiments of the invention in which an exclusive property or privilege
is
claimed are defined as follows:
1. A compound of the formula I
<IMG>
wherein
Q is aryl or heteroaryl ¨ with the exception of pyrimidine;
A and B are identical or different and independently of one another are each
i) H, Hal, -OH, -NR3R4, -CN, or -NO2,
ii) C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C6-
cycloalkyl or C3-C6-heterocycloalkyl that is optionally substituted with at
least one substituent which at each occurrence is Hal-, -OH, C3-C6-
heterocycloalkyl-, -NR3R4, -SO2NR3R4, -SO2R3 or -(CO)-NR3-L, wherein the
C3-C6-heterocycloalkyl optionally comprises in the ring:
at least one nitrogen, oxygen or sulfur atom or any combination thereof,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or
any combination thereof, or
iii) -NR3(CO)-L, -NR3(CO)-NR3-L, -(CO)-R6, -O-(CH2)p-R6, -(CO)-(NR3)-L,
-NR3(CS)-NR3R4, -NR3(SO2)-L, -(SO2)-NR3R4, -NR3(CO)NR3R4, -(CO)NR3R4,
-CO2R7, -NR3(SO2)R4 or -O-(CH2)p-aryl, or

-177-
A and B together form a Q-fused C5-C7-cycloalkyl or C5-C7-heterocycloalkyl
ring,
wherein the latter comprises at least one oxygen or one nitrogen atom in the
ring, and optionally comprises additionally in the ring:
at least one oxygen, nitrogen or sulfur atom,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or
any combination thereof,
P is 0 to 4,
L is C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl or C3-C6-
heterocycloalkyl that is
optionally substituted with at least one substituent which at each occurrence
is OH-,
C1-C6-alkyl-, C1-C6-haloalkyl-, C1-C6-hydroxyalkoxy-, C1-C6-alkoxy-, C1-C6-
haloalkoxy-, C1-C6-alkoxyalkoxy-, C3-C6-heterocycloalkyl-, or -NR3R4, wherein
the
C3-C6 heterocycloalkyl optionally comprises in the ring:
at least one nitrogen, oxygen or sulfur atom, or any combination thereof,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or
any combination thereof;
R1 and R2 are identical or different and independently of one another are each
j) -H, or
jj) C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-
alkenyl, C2-
C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl that
is
optionally substituted with at least one substituent which at each occurrence
is
Hal, -OH, -CN, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy,
C1-
C6-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, C2-C6-alkynyl,
aryl,
aryloxy, heteroaryl, -S-C1-C6-alkyl, -(CO)-R6, -NR3R4, -NR3(CO)-L, -NR3COOR7,
-COOR7, -NR3CONR3R4, -NR3SO2R4, -SO2NR3R4 , -CONR3R4- or -SO2R3, wherein the
C3-C6-heterocycloalkyl optionally comprises in the ring:

-178-
at least one nitrogen, oxygen or sulfur atom, or any combination thereof,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or
any combination thereof, or
-(CH2)r-R8 radical, wherein r is a number 0-3, and R8 is a radical
<IMG>
wherein the aryl, heteroaryl, C3-C6-cycloalkyl or C3-C6-heterocycloalkyl
substituent
optionally present in R1 or R2 is optionally substituted with at least one
substituent
which at each occurrence is -Hal, -CN, - OH, -C1-C6-alkyl, C1-C6-haloalkyl, -
C1-C6-
alkoxy, C1-C6-haloalkoxy, -C1-C6-hydroxyalkyl, -C3-C6-cycloalkyl, -NO2, -NH2,
-NR3R4, -CONR3R4, -NR3COR4, NR3SO2R4, -COR6, CO2R7, -SO2NR3R4, -SR3, SOR3,
-SO2R3, -OR3, or -O(CH2)p R6,
wherein two or more aryl or heteroaryl groups may not be substituents on the
same carbon atom in R1 or R2; or
R1 and R2 together form a C3-C6-heterocycloalkyl ring which comprises at least
one
nitrogen atom in the ring and optionally comprises additionally in the ring,
at least one nitrogen, oxygen or sulfur atom,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or
any combination thereof,
wherein the ring formed by R1 and R2 is optionally substituted with at least
one
substituent which at each occurrence is -CN, -Hal, -OH, C1-C6-alkyl, C1-C6-
haloalkyl, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxyalkyl, C1-C6-

- 179 -
haloalkoxyalkyl, C1-C6-haloalkoxy-, -NR3R4, -CONR6R7, -(CO)-R6 or -COOR7,
or
aryl or heteroaryl that is optionally substituted with at least one
substituent
which at each occurrence is Hal-, C1-C6-alkoxy-, C1-C6-haloalkoxy- or
-(CO), or
any combination thereof,
R3 and R4 are identical or different and independently of one another are each
j) -H, or
jj) C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-
alkenyl, C2-
C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl that
is
optionally substituted with at least one substituent which at each occurrence
is Hal-,
-OH-, -CN-, C1-C6-alkyl-, C1-C6-haloalkyl-, C1-C6-alkoxy-, C1-C6-haloalkoxy-,
C1-C6-
hydroxyalkyl-, C3-C6-cycloalkyl-, C3-C6 heterocycloalkyl-, C2-C6-alkynyl-,
aryl-,
aryloxy-, heteroaryl-, -NR6R7-, -CONR6R7-, -(CO)-R6- or -COOR7, wherein the C3-
C6-heterocycloalkyl optionally comprises in the ring
at least one nitrogen, oxygen or sulfur atom, or any combination thereof,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or
any combination thereof, or
R3 and R4 together form a C3-C6-heterocycloalkyl ring which comprises at least
one
nitrogen atom in the ring and optionally comprises additionally in the ring
at least one nitrogen, oxygen or sulfur atom,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or
any combination thereof,

-180-
wherein the ring formed by R3 and R4 is optionally substituted with at least
one substituent which at each occurrence is
(a) -CN, -Hal, -OH, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, C1-C6-
hydroxyalkyl, C1-C6-alkoxyalkyl, C1-C6-haloalkoxyalkyl, or C1-C6-
haloalkoxy-,
(b) -NR6R7, -CONR6R7, -(CO)-R6 or -COOR7, or
(c) aryl or heteroaryl that is optionally substituted with at least one
substituent which at each occurrence is Hal, C1-C6-alkoxy, C1-C6-
haloalkoxy or -(CO)-R6, or
(d) any combination thereof,
R6 and R7 are identical or different and independently of one another are each
j) ¨H, or
jj) C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-
alkenyl,
C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl
that is
optionally substituted with at least one substituent which at each occurrence
is Hal,
-OH, or -CN, wherein the C3-C6-heterocycloalkyl optionally comprises in the
ring
at least one nitrogen, oxygen or sulfur atom, or any combination thereof,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or
any combination thereof, or
an isomer, diastereomer, enantiomer or salt thereof.
2. The
compound as claimed in claim 1, wherein R1 and R2 are identical or different
and
independently of one another are each
j) ¨H, or
jj) C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-
alkenyl, C2-C6-
alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl that is optionally
substituted with at least

-181-
one substituent which at each occurrence is Hal, -OH, -CN, C1-C6-alkyl, C1-C6-
haloalkyl,
C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6
heterocycloalkyl, C2-C6-alkynyl, aryl, aryloxy, heteroaryl, -S-C1-C6-alkyl, -
(CO)-R6,
-NR3R4, -NR3(CO)-L- or -NR3COOR7, wherein the C3-C6-heterocycloalkyl
optionally
comprises in the ring
at least one nitrogen, oxygen or sulfur atom, or any combination thereof,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or
any combination thereof, or
R1 and R2 together form a C3-C6-heterocycloalkyl ring which comprises at least
one
nitrogen atom in the ring and optionally additionally comprises in the ring
at least one nitrogen, oxygen or sulfur atom,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or
any combination thereof,
wherein the ring formed by R1 and R2 is optionally substituted with at least
one
substituent which at each occurrence is
(a) -CN, -Hal, -OH, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, C1-C6-
hydroxyalkyl, C1-C6-alkoxyalkyl, C1-C6-haloalkoxyalkyl, C1-C6-haloalkoxy,
-NR3R4, -CONR6R7, -(CO)-R6 or -COOR7, or
(b) aryl or heteroaryl that is optionally substituted with at least one
substituent
which at each occurrence is Hal-, C1-C6-alkoxy-, C1-C6-haloalkoxy- or -(CO)-
R6, or
(c) any combination thereof.
3. The compound as claimed in claim 1, where R1 and R2 are identical or
different and
independently of one another are

- 182 -
j) -H or
jj) C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C6-
cycloalkyl, or
C3-C6-heterocycloalkyl that is optionally substituted with at least one
substituent which at
each occurrence is Hal, -OH, -CN, C1-C6-alkyl, C1-C2-haloalkyl, C1-C6-alkoxy,
C1-C2-
haloalkoxy, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl, aryloxy,
heteroaryl, -S-C1-
C6-alkyl, -(CO)-R6, -NR3R4, -NR3(CO)-L, -NR3COOR7, -COOR7, -NR3SO2R4, -
SO2NR3R4,
-CONR3R4 or -SO2R3 or
-(CH2)R8 radical where R8 is a radical
<IMG>
wherein the aryl, heteroaryl, C3-C6-cycloalkyl or C3-C6-heterocycloalkyl
substituent
optionally present in R1 or R2 is optionally substituted with at least one
substituent
which at each occurrence is -Hal, -CN, - OH, -C1-C6-alkyl, -C1-C2-haloalkyl,
-C1-C6-alkoxy, -C1-C2-haloalkoxy, -C1-C6-hydroxyalkyl, -C3-C6-cycloalkyl, -
NO2,
-NH2, -C1-C6-haloalkyl, -NR3R4, -CONR3R4, -NR3COR4, NR3SO2R4, -COR6, CO2R7,
-SO2NR3R4, -SR3, SOR3, --SO2R3, -OR3, or -O(CH2)p R6,
wherein two or more aryl or heteroaryl groups in R1 or R2 may not be
substituents of
the same carbon atom.
4. The
compound as claimed in claim 1 or 2, wherein R1 and R2 are identical or
different
and independently of one another are each
j) -H, or
jj) C1-C6-alkyl, C1-C6-haloalkyl-, C1-C6-alkoxy, C1-C6-haloalkoxy-, C2-C6-
alkenyl, C2-C6-
alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl that is
optionally
substituted with at least one substituent which at each occurrence is Hal, -
OH, -CN, C1-
C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-hydroxyalkyl,
C3-C6-
cycloalkyl, C3-C6 heterocycloalkyl, C2-C6-alkynyl, aryloxy, -S-C1-C6-alkyl, -
(CO)-R6,
-NR3R4, -NR3(CO)-L or -NR3COOR7, wherein the C3-C6-heterocycloalkyl optionally
comprises in the ring

- 183 -
at least one nitrogen, oxygen or sulfur atom, or any combination thereof,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or
any combination thereof,
wherein the aryl or heteroaryl substituent defined in jj) is optionally
substituted with the
proviso that alkyl is not the substituent, or
R1 and R2 together form a C3-C6-heterocycloalkyl ring which comprises at least
one
nitrogen atom in the ring and optionally additionally comprises in the ring
at least one nitrogen, oxygen or sulfur atom,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or
any combination thereof,
wherein the ring formed by R1 and R2 is optionally substituted with at least
one
substituent which at each occurrence is
(a) -CN, -Hal, -OH, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, C1-C6-
hydroxyalkyl, C1-C6-alkoxyalkyl, C1-C6-haloalkoxyalkyl, C1-C6-haloalkoxy,
-NR3R4, -CONR6R7, -(CO)-R6 or -COOR7, or
(b) aryl or heteroaryl that is optionally substituted with at least one
substituent
which at each occurrence is Hal-, C1-C6-alkoxy-, C1-C6-haloalkoxy- or -(CO)-
R6, or
(c) any combination thereof.
5. The compound as claimed in claim 3 or 4, wherein Q is phenyl, pyridyl,
thiophenyl,
furyl, imidazolyl, or pyrazolyl that is optionally substituted with at least
one substituent
which at each occurrence is -OH, Hal, -CN, alkyl, -OR6 or -NR3R4.
6. The compound as claimed in claim 5, where R1 and R2 are identical or
different and
independently of one another are each -H or NR3R4-substituted C1-C4-alkyl,

-184-
optionally additionally substituted with at least one substituent which at
each
occurrence is -Hal, -OH, -CN, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-
C6-
haloalkoxy, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6 heterocycloalkyl, C2-
C6-
alkynyl, aryl, aryloxy, heteroaryl, -S-C1-C6-alkyl, -(CO)-R6, -NR3(CO)-L, or -
NR3COOR7, wherein R3 and R4 may optionally, identically or differently, be C1-
C6-
alkyl or C1-C6-haloalkyl, wherein R3 and R4 may together form a C3-C6-
heterocycloalkyl ring which comprises at least one nitrogen atom in the ring
and
optionally additionally comprises in the ring
at least one nitrogen, oxygen or sulfur atom,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or
any combination thereof,
and wherein R6 and R7 are each independently -H, -OH, C1-C6-alkoxy, C1-C6-
haloalkoxy or C1-C3-alkyl.
7. The compound as claimed in any one of claims 1 to 4, wherein R1 is -H or
C1-C3-
alkyl, wherein R2 is NR3R4-substituted C3-C4 alkyl that is optionally
additionally
substituted with at least one substituent which at each occurrence is Hal, -
OH, -CN, C1-
C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-hydroxyalkyl,
C3-C6-
cycloalkyl, C3-C6 heterocycloalkyl, C2-C6-alkynyl, aryl, aryloxy, heteroaryl, -
S-C1-C6-
alkyl, -(CO)-R6, -NR3(CO)-L or -NRCOOR7, wherein R3 and R4 are each
independently
C1-C6-alkyl or C1-C6-haloalkyl that is optionally substituted with at least
one
substituent which at each occurrence is Hal, -OH, -CN, C1-C6-alkyl, C1-C6-
haloalkyl,
C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6
heterocycloalkyl, C2-C6-alkynyl, aryl, aryloxy, heteroaryl, -NR6R7, -CONR6R7, -
(CO)-R6
or -COOR7, or R3 and R4 together form a C3-C6-heterocycloalkyl ring which
comprises at least one nitrogen atom in the ring and optionally additionally
comprises
in the ring
at least one nitrogen, oxygen or sulfur atom,
at least one -(CO)- or -(SO2)- group, or
at least one double bond, or

-185-
any combination thereof,
and wherein R6 and R7 are each independently -H, -OH, C1-C6-alkoxy, C1-C6-
haloalkoxy, or C1-C3 alkyl.
8. The compound as claimed in any one of claims 1 to 7, wherein R1 or R2 is
-H.
9. The compound as claimed in claim 1, which is:
(3-phenylimidazo[1,2-b]pyridazin-6-yl)-(3-pyrrolidin-1-ylpropyl)amine;
(3-morpholin-4-ylpropyl)-(3-phenylimidazo[1,2-b]pyridazin-6-y)amine;
(3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)-(3-pyrrolidin-1-
ylpropyl)amine;
(3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)-(3-morpholin-4-
ylpropyl)amine;
[3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl]pyridin-3-
ylmethylamine;
(3-phenylimidazo[1,2-b]pyridazin-6-yl)pyridin-3-ylmethylamine;
(3-imidazol-1-ylpropyl)-(3-phenylimidazo[1,2-b]pyridazin-6-yl)amine;
(4-fluorobenzyl)-(3-phenylimidazo[1,2-b]pyridazin-6-yl)amine;
cyclohexylmethyl-(3-phenylimidazo[1,2-b]pyridazin-6-yl)amine;
(2,4-difluorobenzyl)-(3-phenylimidazo[1,2-b]pyridazin-6-yl)amine;
[3-(5-methyl-1H-pyrazol-4-yl)propyl]-(3-phenylimidazo[1,2-b]pyridazin-6-
yl)amine;
1-[2-(3-phenylimidazo[1,2-b]pyridazin-6-ylamino)ethyl]imidazolidin-2-one,
(2-morpholin-4-ylethyl))-(3-phenylimidazo[1,2-b]pyridazin-6-yl)amine;
N*1,N*1*-diethyl-N*4-(3-phenylimidazo[1,2-b]pyridazin-6-yl)pentane-1,4-
diamine;
N,N-diethyl-N'-(3-phenylimidazo[1,2-b]pyridazin-6-yl)propane-1,3-diamine;
(3-phenylimidazo[1,2-b]pyridazin-6-yl)-(2-pyrrolidin-1-ylethyl)amine;
[3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl]pyridin-3-ylmethylamine;
[3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl]-(3-imidazol-1-ylpropyl)amine;
3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)-(4-fluorobenzyl)amine;
3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexylmethylamine;
3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)-(2,4-difluorobenzyl)amine;
1-{2-[3-(3-phenyl)imidazo[1,2-b]pyridazin-6-ylamino]ethyl}imidazolidin-2-one;

- 185a -
N*4*-[3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl]-N*1*,N*1*-diethylpentane-
1,4-diamine,
N'-[3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl]-N,N-diethylpropane-1,3-
diamine;
[3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl]-(2-pyrrolidin-1-
ylethyl)amine;
(3-imidazol-1-ylpropyl)-[3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-
yl]amine;
(4-fluorobenzyl)-[3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-
yl]amine;
cyclohexylmethyl-[3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-
yl]amine,
(2,4-difluorobenzyl)-[3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-
yl]amine,
[3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl]-[5-methyl-1H-
pyrazol-
4-yl)propyl]amine;
1-{2-[3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-
ylamino]ethyl}imidazolidin-2-one;
(3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)-(2-morpholin-4-
ylethyl)amine;
N*1, N*1*-diethyl-N*4-[3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-
yl]pentane-1,4-diamine;
N,N-diethyl-N'-[3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-
yl]propane-1,3-diamine;
[3-(1-methyl-1H-pyrazol-4-yl)imidazo[1 ,2-b]pyridazin-6-yl]-(2-pyrrolidin-1-
ylethyl)amine;
pyridin-3-ylmethyl-(3-thiophen-3-ylimidazo[1,2-b]pyridazin-6-yl)amine;
(4-fluorobenzyl)-(3-thiophen-3-ylimidazo[1,2-b]pyridazin-6-yl)amine;
cyclohexylmethyl-(3-thiophen-3-ylimidazo[1,2-b]pyridazin-6-yl)amine;
(2,4-difluorobenzyl)-(3-thiophen-3-ylimidazo[1,2-b]pyridazin-6-yl)amine;
[3-(5-methyl-1H-pyrazol-4-yl)propyl]-(3-thiophen-3-ylimidazo[1,2-b]pyridazin-6-
yl)amine;
1-[2-(3-thiophen-3-ylimidazo[1,2-b]pyridazin-6-ylamino)ethyl]imidazolidin-2-
one,

-185b-
(2-morpholin-4-ylethyl)-(3-thiophen-3-ylimidazo[1,2-b]pyridazin-6-yl)amine;
N*1,N*1*-diethyl-N*413-thiophen-3-ylimidazo[1,2-b]pyridazin-6-yl]pentane-1,4-
diamine;
N,N-diethyl-N'-(3-thiophen-3-ylimidazo[1,2-b]pyridazin-6-yl]propane-1,3-
diamine; or
(2-pyrrolidin-1-ylethyl)-(3-thiophen-3-ylimidazo[1,2-b]pyridazin-6-yl)amine.
10. The compound as claimed in claim 1, which is:
(3-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-(3-pyrrolidin-1-yl-propyl)-amine;

-186-
<IMG>
(3-Morpholin-4-yl-propyl)-(3-phenyl-
imidazo[1,2-b]pyridazin-6-yl)-amine ;
<IMG>
[3-(3-chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yl]-(3-pyrrolidin-1-yl-
propyl)-amine ;
<IMG>
(3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yl]-(3-morpholin-4-yl-
propyl)-amine ;
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yl]-methyl-(3-morpholin
-4-yl-propyl)-amine ;
<IMG>
3-[3-(3-Chloro-phenyl)-imidazo[1,2-
b]pyridazin-6-ylamino]-pyrrolidine-
1-carboxylic acid tert-butyl ester ;

- 187 -
<IMG>
N-{3-[6-(3-Morpholin-4-yl-propylami
no)-imidazo[1,2-b]pyridazin-3-yl]-p
henyl}-acetamide ;
<IMG>
(S)-N*4*-[3-(3-Chloro-phenyl)-imida
zo[1,2-b]pyridazin-6-yl]-N1*,N*1*-
diethyl-pentane-1,4-diamine ;
<IMG>
(R)-N*4*-[3-(3-Chloro-phenyl)-imida
zo[1,2-b]pyridazin-6-yl]-N*1*,N*1*-
diethyl-pentane-1,4-diamine ;
<IMG>
4-[3-(3-Chloro-phenyl)-imidazo[1,2-
b]pyridazin-6-yl]-piperazine-1-carb
oxylic acid tert-butyl ester ;
<IMG>
2-[3-(3-Chloro-phenyl)-imidazo[1,2-
b]pyridazin-6-ylamino]-ethanesulfon
ic acid dimethylamide ;

-188-
<IMG>
N'-[3-(3-Chloro-4-methyl-phenyl)-im
idazo[1,2-b]pyridazin-6-yl]-N,N-die
thyl-propane-1,3-diamine ;
<IMG>
(2-Pyridin-2-yl-ethyl)-[3-(3,4,5-trimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-
yl-amine ;
<IMG>
1-(3-{6-[(Pyridin-4-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-
ethanone ;
<IMG>
1-[3-(6-Propylamino-imidazo[1,2-b]pyridazin-3-yl)-phenyl]-ethanone ;
<IMG>
[3-(3,5-Dimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-
yl)-amine ;
<IMG>
4-[6-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenol ;

- 189 -
<IMG>
(Tetrahydro-pyran-4-yl)-[3-(3-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazin-
6-yl]-amine;
<IMG>
(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-(tetrahydro-pyran-4-yl)-
amine ;
<IMG>
[3-(6-Methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-
yl)-amine ;
<IMG>
[3-(2-Methoxy-pyridin-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-
yl)-amine;
<IMG>
[3-(3-Methanesulfonyl-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-
4-yl)-amine ;
[3-( 1 -Methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-pyridin-3-
ylmethyl-amine ;

- 190 -
<IMG>
(3-Phenyl-imidazo[1,2-b]pyridazin-6
-yI)-pyridin-3-ylmethyl-amine;
<IMG>
(3-Imidazol-1-yI-propyl)-(3-phenyl-
imidazo[1,2-b]pyridazin-6-yl)-amine;
<IMG>
(4-Fluoro-benzyI)-(3-phenyl-imidazo
[1,2-b]pyridazin-6-yI)-amine;
<IMG>
Cyclohexylmethyl-(3-phenyl-imidazo
[1,2-b]pyridazin-6-yI)-amine;
<IMG>
(2,4-Difluoro-benzyI)-(3-phenyl-
imidazo[1,2-b]pyridazin-6-yI)-amine;

- 191 -
<IMG>
[3-(5-Methyl-1H-pyrazol-4-yl)-propyl]-
(3-phenyl-imidazo[1,2-b]pyridazin-6-yl)
-amine;
<IMG>
1-[2-(3-Phenyl-imidazo[1,2-b]
pyridazin-6-ylamino)-ethyl]-
imidazolidin-2-one;
<IMG>
(2-Morpholin-4-yl-ethyl)-(3-phenyl-
imidazo[1,2-b]pyridazin-6-yl)-amine;
<IMG>
N*1*,N*1*-Diethyl-N*4*-(3-phenyl-
imidazo[1,2-b]pyridazin-6-yl)-pentane

-192-
<IMG>
N,N-Diethyl-N'-(3-phenyl-imidazo
[1,2-b]pyridazin-6-yl)-propane-1,3-
diamine ;
<IMG>
(3-Phenyl-imidazo[1,2-b]pyridazin-
6-yl)-(2-pyrrolidin-1-yl-ethyl)-amine ;
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yl]-pyridin-3-ylmethyl-
amine ;
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yl]-(3-imidazol-1-yl-
propyl)-amine ;

-193-
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yl]-(4-fluoro-benzyl)-
amine ;
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yl]-cyclohexylmethyl-
amine ;
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yl]-(2,4-difluoro-benzyl)-
amine ;
<IMG>
1-{2-[3-(3-Chloro-phenyl)-imidazo
[1,2-b]pyridazin-6-ylamino]-ethyl)-
imidazolidin-2-one ;

- 194 -
<IMG>
N*4*-[3-(3-Chloro-phenyI)-imidazo
[1 ,2-b]pyridazin-6-yl]-N*1*,N*1*-
diethyl-pentane-1,4-diamine
<IMG>
N'-[3-(3-Chloro-phenyI)-imidazo
[1,2-b]pyridazin-6-yI]-N,N-diethyl-
propane-1 ,3-diamine
<IMG>
[3-(3-Chloro-phenyl)-imidazo
[1 ,2-b] pyridazin-6-yI]-(2-pyrrolidin-
1-yI-ethyl)-amine
<IMG>
(3-Imidazol-1 -yl-propyI)-[3-(1-
methyl-1H -pyrazol-4-yI)-imidazo
[1 ,2-b] pyridazin-6-yI)-amine

- 195 -
<IMG>
(4-Fluoro-benzyl)-(3-(1 -methyl-1H-
pyrazol-4-yl)-imidazo[1,2-b]-
pyridazin-6-yl]-amine
<IMG>
Cyclohexylmethyl-[3-(1 -methyl-1H-
pyrazol-4-yl)-imidazo[1,2-b]pyridazin-
6-yI]-amine
<IMG>
(2,4-Difluoro-benzyl)-[3-(1 -methyl-
1H-pyrazol-4-yl)-imidazo[1 ,2-b]-
pyridazin-6-yl]-amine
<IMG>
[3-(1 -Methyl-1 H-pyrazol-4-yl)-imidazo-
[1,2-b]pyridazin-6-yl]-[3-(5-methyl-
1H-pyrazol-4-yl)-propyl]-amine

- 196 -
<IMG>
1-{2-[3-(1 -Methyl-1H-pyrazol-4-yl)-
imidazo[1,2-b]pyridazin-6-ylamino]-
ethyl}-imidazolidin-2-one
<IMG>
[3-(1 -Methyl-1 H-pyrazol-4-yl)-
imidazo[1,2-b]pyridazin-6-yl]-
(2-morpholin-4-yl-ethyl)-amine
<IMG>
N*1*,N*1*-Diethyl-N*4*-[3-(1-methyl
-1 H-pyrazol-4-yl)-imidazo[1,2-b]-
pyridazin-6-yl]-pentane-1,4-diamine
<IMG>
N,N-Diethyl-N'-[3-(1 -methyl-1 H-
pyrazol-4-yl)-imidazo[1,2-b]pyridazin-
6-yl]-propane-1,3-diamine

- 197 -
<IMG>
[3-(1-Methyl-1H-pyrazol-4-yl)-
imidazo[1,2-b]pyridazin-6-yl]-
(2-pyrrolidin-1-yl-ethyI}-amine
<IMG>
Pyridin-3-ylmethyl-(3-thiophen-3-
yl-imidazo[1,2-b]pyridazin-6-yl)-
amine
<IMG>
(3-Imidazol-1-yl-propyl)-(3-thiophen-
3-yl-imidazo[1,2-b]pyridazin-6-yl)-
amine
<IMG>
(4-Fluoro-benzyI)-(3-thiophen-3-yl-
imidazo[1,2-b]pyridazin-6-yI)-amine

-198-
<IMG>
Cyclohexylmethyl-(3-thiophen-3-yl-
imidazo[1,2-b]pyridazin-6-yl)-amine ;
<IMG>
(2,4-Difluoro-benzyl)-(3-thiophen-3-
yl-imidazo[1,2-b]pyridazin-6-yl)-
amine ;
<IMG>
[3-(5-Methyl-1H-pyrazol-4-yl)-
propyl]-(3-thiophen-3-yl-imidazo-
[1,2-b]pyridazin-6-yl)-amine ;
<IMG>
1-[2-(3-Thiophen-3-yl-imidazo-
[1,2-b]pyridazin-6-ylamino)-ethyl]-
imidazolidin-2-one ;

-199-
<IMG>
(2-Morpholin-4-yl-ethyl)-(3-
thiophen-3-yl-imidazo[1,2-b]
pyridazin-6-yl)-amine ;
<IMG>
N*1*,N*1*-Diethyl-N*4*-(3-thiophen-
3-yl-imidazo[1,2-b]pyridazin-6-yl)-
pentane-1,4-diamine ;
<IMG>
N,N-Diethyl-N'-(3-thiophen-3-yl-
imidazo[1,2-b]pyridazin-6-yl)-
propane-1,3-diamine ;
<IMG>
(2-Pyrrolidin-1-yl-ethyl)-(3-
thiophen-3-yl-imidazo[1,2-b]-
pyridazin-6-yl)-amine ;

- 200 -
<IMG>
[3-(3-Methoxy-phenyI)-imidazo[1,2-b
]pyridazin-6-yI]-methyl-(2-pyridin-
2-yl-ethyl)-amine
<IMG>
Methyl-(2-pyridin-2-yl-ethyl)-[3-(3
-trifluoromethoxy-phenyl)-imidazo[1
,2-b]pyridazin-6-yI]-amine
<IMG>
[3-(3,4-Dichloro-phenyI)-imidazo[1,
2-b]pyridazin-6-yl]--methyl-(2-pyrid
in-2-yl-ethyl)-amine
<IMG>
[3-(3-Chloro-4-fluoro-phenyl)-imida
zo[1,2-b]pyridazin-6-yl]-methyl-(2-
pyridin-2-yl-ethyl)-amine

- 201 -
<IMG>
Methyl-(3-naphthalen-2-yI-imidazo[1
,2-b]pyridazin-6-yI)-(2-pyridin-2-y
I-ethyl)-amine
<IMG>
[3-(3-Methoxy-phenyI)-imidazo[1,2-b
]pyridazin-6-yI)-(2-pyridin-2-yl-et
hyl)-amine
<IMG>
[3-(3,4-Dichloro-phenyI)-imidazo[1,
2-b]pyridazin-6-yI]-(2-pyridin-2-yl
-ethyl)-amine
<IMG>
3-[6-(2-Pyridin-2-yl-ethylamino)-im
idazo[1,2-b]pyridazin-3-yI]-benzoni
trile

- 202 -
<IMG>
(3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yl]-(2-(6-methyl-pyridi
n-2-yl-ethyl]-amine
<IMG>
[2-(6-Methyl-pyridin-2-yl)-ethyl]-[
3-(3-trifluoromethoxy-phenyI)-imida
zo[1,2-b)pyridazin-6-yI]-amine
<IMG>
[2-(6-Methyl-pyridin-2-yl)-ethyl]-(
3-naphthalen-2-yl-imidazo[1,2-b]pyr
idazin-6-yI)-amine
<IMG>
(3-(3,4-DichIoro-phenyl)-imidazo[1,
2-b]pyridazin-6-yl]-[2-(4-methyl-py
ridin-2-yl)-ethyl]-amine

-203-
<IMG>
[2-(4-Methyl-pyridin-2-yl)-ethyl]-(
3-naphthalen-2-yl-imidazo[1,2-b]pyr
idazin-6-yl)-amine ;
<IMG>
[2-(3-Methyl-pyridin-2-yl)-ethyl]-[
3-(3-trifluoromethoxy-phenyl)-imida
zo[1,2-13]pyridazin-6-yl]-amine ;
<IMG>
[3-(3-Methoxy-phenyl)-imidazo[1,2-b
]pyridazin-6-yl]-[2-(5-methyl-pyrid
in-2-yl)-ethyl]-amine ;
<IMG>
[2-(5-Methyl-pyridin-2-yl)-ethyl]-[
3-(3-trifluoromethoxy-phenyl)-imida
zo[1,2-b]pyridazin-6-yl]-amine ;

-204-
<IMG>
[3-(3,4-Dichloro-phenyl)-imidazo[1,
2-b]pyridazin-6-yl]-(2-(5-methyl-py
ridin-2-yl)-ethyl]-amine ;
<IMG>
[3-(3-Chloro-4-fluoro-phenyl)-imida
zo[1,2-b]pyridazin-6-yl]-[2-(5-meth
yl-pyridin-2-yl)-ethyl]-amine ;
<IMG>
[3-(3,4-Dichloro-phenyl)-imidazo[1,
2-b]pyridazin-6-yl]-[2-(3-methyl-py
ridin-2-yl)-ethyl]-amine ;
<IMG>
[3-(3,4-Dichloro-phenyl)-imidazo[1,
2-b]pyridazin-6-yl]-(2-(6-methyl-py
ridin-2-yl)-ethyl]-amine ;

-205-
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yI]-(2-pyrazin-2-yl-eth
yI)-amine
<IMG>
[3-(3-Methoxy-phenyl)-imidazo[1,2-b
]pyridazin-6-yI]-(2-pyrazin-2-yl-et
hyl)-amine
<IMG>
[3-(3-Chloro-4-fluoro-phenyl)-imida
zo[1,2-b]pyridazin-6-yI]-(2-pyrazin
-2-yl-ethyl)-amine
<IMG>
(3-Naphthalen-2-yl-imidazo[1,2-b]py
ridazin-6-yI)-(2-pyrazin-2-yl-ethyl
)-amine

-206-
<IMG>
(3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yI]-[2-(4-methyl-pyridi
n-2-yI)-ethyl]-amine
<1MG>
[2-(4-Methyl-pyridin-2-yl)-ethyl]-[
3-(3-trifluoromethoxy-phenyI)-imida
zo[1,2-b]pyridazin-6-yl]-amine
<IMG>
[3-(3-Chloro-4-fluoro-phenyl)-imida
zo[1,2-b]pyridazin-6-yI]-[2-(4-meth
yI-pyridin-2-yl)-ethyl]-amine
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yI]-(2-pyrazol-1-yl-eth
yI)-amine

-207-
<IMG>
[3-(3-Methoxy-phenyI)-imidazo[1,2-b
]pyridazin-6-yI]-(2-pyrazol-1-yl-et
hyl)-amine
<IMG>
(2-Pyrazol-1-yI-ethyl)-[3-(3-triflu
oromethoxy-phenyI)-imidazo[1,2-b]py
ridazin-6-yl]-amine
<IMG>
(3-(3,4-Dichloro-phenyl)-imidazo[1,
2-b]pyridazin-6-yI]-(2-pyrazol-1-yl
-ethyl)-amine
<IMG>
3-[6-(2-Pyrazol-1-yl-ethylamino)-im
idazo[1,2-b]pyridazin-3-yl]-benzoni
trile ;

-208-
<IMG>
[3-(3-Chloro-4-fluoro-phenyI)-imida
zo[1,2-b]pyridazin-6-yl]-(2-pyrazol
-1-yl-ethyl)-amine
<IMG>
(3-Naphthalen-2-yI-imidazo[1,2-b]py
ridazin-6-yl)-(2-pyrazol-1-yl-ethyl
)-amine
<IMG>
[2-(1-Methyl-1H-imidazol-4-yl)-ethy
l]-(3-(3-trifluoromethoxy-phenyl)-i
midazo[1,2-b]pyridazin-6-yl]-amine
<IMG>
3-{6-[2-(1-Methyl-I H-imidazol-4-yl)
-ethylamino]-imidazo[1,2-b]pyridazi
n-3-yI)-benzonitrile;

-209-
<IMG>
[2-(1-Methyl-1H-imidazol-4-yl)-ethy
l]-(3-naphthalen-2-yl-imidazo[1,2-b
]pyridazin-6-yI)-amine
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yl]-(2-[1,2,4]triazol-1
-yl-ethyl)-amine;
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yl]-methyl-(2-pyridin-2
-yl-ethyl)-amine
(4-[6-(2-Hydroxy-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenol;
<IMG>
4-[6-((R)-2-Hydroxy-1-methyl-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenol;

210

-211-
<IMG>
2-[3-(3-Methanesulfonyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-ethanol;
<IMG>
2-[3-(3-Methylsulfanyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-ethanol;
<IMG>
[3-(1H-1ndol-5-yl)-imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-3-yl]-ethyl)-amine
;
<IMG>
(2-Pyridin-3-yl-ethyl)-(3-thiophen-3-yl-imidazo[1,2-b]pyridazin-6-yl)-amine;
<IMG>
[3-(3-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-3-yl-ethyl)-
amine;

-212 -
<IMG>
(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-(2-pyridin-2-yl-ethyl)-amine
;
<IMG>
[3-(4-Chloro-phenyI)-imidazo[1,2-b]
pyridazin-6-yI]-(2-pyridin-2-yl-eth
yl)-amine ;
<IMG>
[3-(3,4-Dimethyl-phenyI)-imidazo[1,
2-b]pyridazin-6-yI]-(2-pyridin-2-yI
-ethyl)-amine ;
<IMG>
(2-Pyridin-2-yl-ethyl)-[3-(3-trifluoromethoxy-phenyl)-imidazo[1 ,2-
b]]pyridazin-6-yl]-amine ;
<IMG>
[3-(3-Chloro-4-fluoro-phenyl )imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-3-yl-
ethyl)-amine ;

-213-
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-2-yl-ethyl)-
amine ;
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yl]-(2-pyridin-3-yl-eth
yl)-amine ;
<IMG>
(2-Pyridin-2-yl-ethyl)43-(3-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazin-6-
yl]-amine ;
<IMG>
[3-(3-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-2-yl-ethyl)-
amine ;
<IMG>
[3-(4-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-2-yl-ethyl)-
amine ;

-214-
<IMG>
[3-(4-Methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-2-yl-
ethyl)-amine ;
<IMG>
4-[3-(3-Chloro-4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-
cyclohexanol ;
<IMG>
1-{3-[6-(2-Pyridin-2-yl-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
ethanone ;
<IMG>
N-{3-[6-(2-Pyridin-2-yl-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
methanesulfonamide ;
<IMG>
4-[6-(2-Pyridin-2-yl-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzonitrile ;

-215-
<IMG>
(2-Pyridin-2-yl-ethyl)-(3-p-tolyl-imidazo[1,2-b]pyridazin-6-yl)-amine ;
<IMG>
(3-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-(2-pyridin-2-yl-ethyl)-amine ;
<IMG>
(3-Naphthalen-1-yl-imidazo[1,2-b]pyridazin-6-yl)-(2-pyridin-2-yl-ethyl)-amine
;
<IMG>
(3-Benzofuran-2-yl-imidazo[1,2-b]pyridazin-6-yl)-(2-pyridin-2-yl-ethyl)-amine
;
<IMG>
[3-(3-Chloro-4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-2-yl-
ethyl)-amine ;

-216-
<IMG>
(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-(2-pyridin-2-yl-ethyl)-
amine ;
<IMG>
(3-Benzo[1,3]dioxol-5-yl-imidazo[1,2-b]pyridazin-6-yl)-(2-pyridin-2-yl-ethyl)-
amine ;
<IMG>
[3-(4-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-2-yl-ethyl)-
amine ;
<IMG>
(2-Pyridin-3-yl-ethyl)-[3-(3,4,5-trimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-
yl]-amine ;
<IMG>
[3-(4-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-3-yl-ethyl)-
amine ;

- 217 -
<IMG>
(3-Benzo[1,3]dioxol-5-yl-imidazo[1,2-b]pyridazin-6-yl)-(2-pyridin-3-yl-ethyl)-
amine
<IMG>
[3-(4-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-3-yl-ethyl)-
amine
<IMG>
[3-(4-Methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-3-yl-
ethyl)-amine;
<IMG>
(3-Benzofuran-2-yl-imidazo[1,2-b]pyridazin-6-yl)-(2-pyridin-3-yl-ethyl)-amine

- 218 -
<IMG>
(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-(2-pyridin-3-yl-ethyl)-amine
;
<IMG>
(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-(2-pyridin-3-yl-ethyl)-
amine ;
<IMG>
(3-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-(2-pyridin-3-ykethyl)-amine ;
<IMG>
[3-(4-Chloro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-3-yl-ethyl)-
amine ;
<IMG>
4-[6-(2-Pyridin-3-yl-ethylamino)-imidazo[1,2-b]pyridazin-3-yI]-benzonitrile ;

- 219 -
<IMG>
(2-Pyridin-3-yl-ethyl)-{3-(3-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazin-6-
yl]-amine;
<IMG>
[3-(1-Methyl-1H-pyrazol-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-(2-pyridin-3-yl-
ethyl)-amine;
<IMG>
(2-Pyridin-3-yl-ethyl)-(3-thiophen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-amine;
<IMG>
N-{3-[6-(2-Pyridin-3-yl-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
methanesulfonamide
<IMG>
[3-(4-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-furan-2-ylmethyl-amine;

- 220 -
<IMG>
Furan-2-ylmethyl-(3-phenyl-imidazo[1,2-b]pyridazin-6-yI)-amine ;
<IMG>
Furan-2-ylmethyl-[3-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-amine ;
<IMG>
Furan-2-ylmethyl-[3-(1H-indol-5-yl)-imidazo[1,2-b]pyridazin-6-yl]-amine ;
<IMG>
[3-(3-Dimethylamino-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-furan-2-ylmethyl-
amine ;
<IMG>
Furan-2-ylmethyl-[3-(3-methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-amine ;

-221-
<IMG>
N-(3-{6-[(Furan-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-
acetamide ;
<IMG>
(3-{6-[(Furan-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-
methanol ;
<IMG>
4-{6-[(Furan-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-phenol ;
<IMG>
3-{6-[(Furan-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-phenol ;
<IMG>
3-{6-[(Furan-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-benzamide ;

-222-
<IMG>
N-(3-{6-[(Furan-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-
methanesulfonamide ;
<IMG>
4-{6-[(Furan-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-2-methoxy-phenol
<IMG>
1-(3-{6-[(Furan-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-
ethanone ;
<IMG>
Furan-2-ylmethyl-[3-(6-methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
Furan-2-ylmethyl-(3-pyridin-3-yl-imidazo[1,2-b]pyridazin-6-yl)-amine ;

- 223 -
<IMG>
Furan-2-ylmethyl-[3-(5-methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine
<IMG>
Furan-2-ylmethyl-(3-pyridin-4-yl-imidazo[1,2-b]pyridazin-6-yI)-amine
<IMG>
[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-thiophen-2-ylmethyl-
amine
<IMG>
Thiophen-2-ylmethyl-[3-(3,4,5-trimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-
amine

- 224 -
<IMG>
1-(3-{6-[(Thiophen-2-ylmethyl)-amino)-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-
ethanone 3
<IMG>
3-{6-[(Thiophen-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-phenol ;
<IMG>
[3-(5-Methoxy-pyridin-311)-imidazo[1,2-b)pyridazin-6-yl]-thiophen-2-ylmethyl-
amine ;
<IMG>
(4-{6-[(Thiophen-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl]-phenyl)-
methanol -)
<IMG>
N-(2-Hydroxy-ethyl)-3-{6-[(thiophen-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-
3-yl}-benzamide ;

- 225 -
<IMG>
[3-(4-Methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-yl]-thiophen-2-ylmethyl-
amine
<IMG>
(3-Thiophen-2-yl-imidazo[1,2-b]-pyridazin-6-yl)-thiophen-2-ylmethyl-amine
<IMG>
(3-Thiophen-3-yl-imidazo[1,2-b]pyridazin-6-yl)-thiophen-2-ylmethyl-amine
<IMG>
[3-(6-Methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-thiophen-2-ylmethyl-
amine

-226-
<IMG>
[3-(1H-Indo1-5-yl)-imidazo[1,2-b]pyridazin-6-yl]-thiophen-2-ylmethyl-amine ;
<IMG>
[3-(3-Dimethylamino-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-thiophen-2-ylmethyl-
amine ;
<IMG>
[3-(4-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-thiophen-2-ylmethyl-amine ;
<IMG>
[3-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl}-thiophen-2-
ylmethyl-amine ;
<IMG>
(3-Pyridin-3-yl-imidazo[1,2-b]pyridazin-6-yl)-thiophen-2-ylmethyl-amine ;

-227-
<IMG>
N-(3-{6-[(Thiophen-2-ylmethyl)-amino}-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-
acetamide ;
<IMG>
[3-(3-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-thiophen-2-ylmethyl-amine
;
<IMG>
4-{6-[(Thiophen-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-phenol ;
<IMG>
(3-Pyridin-4-yl-imidazo[1,2-b]pyridazin-6-yl)-thiophen-2-ylmethyl-amine ;
<IMG>
2-Methoxy-4-{6-[(thiophen-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-
phenol ;

-228-
<IMG>
3-{6-[(Thiophen-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-benzamide ;
<IMG>
N-(3-{6-[(Thiophen-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-phenyl)-
methanesulfonamide ;
<IMG>
4-{6-[(Thiophen-2-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-benzoic acid
;
<IMG>
[3-(3-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-pyridin-4-ylmethyl-amine ;
<IMG>
Pyridin-4-ylmethyl-[3-(3-trifluoromethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-
yl)-amine ;

-229-
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-pyridin-4-ylmethyl-amine ;
<IMG>
Pyridin-4-ylmethyl-[3-(3-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
[3-(3-Chloro-4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl)-pyridin-4-ylmethyl-
amine ;
<IMG>
(3-Benzofuran--2-yl-imidazo[1,2-b]pyridazin-6-yl)-pyridin-4-ylmethyl-amine ;
<IMG>
[3-(3,4-Dimethyl-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-pyridin-4-ylmethyl-
amine ;

-230-
<IMG>
Pyridin-4-ylmethyl-(3-p-toly-imidazo[1,2-b]pyridazin-6-yl)-amine ,
<IMG>
Pyridin-4-ylmethyl-(3-thiophen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-amine )
<IMG>
(3-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-pyridin-4-ylmethyl-amine
<IMG>
(3-Benzo[1,3]dioxol-5-yl-imidazo[1,2-b]pyridazin-6-yl)-pyridin-4-ylmethyl-
amine ;
<IMG>
(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-pyridin-4-ylmethyl-amine ;

<IMG>

-232-
<IMG>
Pyridin-2-ylmethyl-[3-(3,4,5-trimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
[3-(4-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]pyridin-2-ylmethyl-amine ;
<IMG>
(3-Benzofuran-2-yl-imidazo[1,2-b]pyridazin-6-yl)-pyridin-2-ylmethyl-amine ;
<IMG>
(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-pyridin-2-ylmethyl-amine ;

-233-
<IMG>
[3-(6-Methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-pyridin-2-ylmethyl-
amine ;
<IMG>
(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-pyridin-2-ylmethyl-
amine ;
<IMG>
Pyridin-2-ylmethyl-[3-(3-trifluoromethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-
yl]-amine ;
<IMG>
Pyridin-2-ylmethyl-(3-thiophen-3-yl-imidazo[1,2-b]pyridazin-6-yl)-amine ;
<IMG>
Pyridin-2-ylmethyl-[3-(3-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;

-234-
<IMG>
[3-(3-Dimethylamino-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-pyridin-2-ylmethyl-
amine ;
<IMG>
[3-(3-Chloro-4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-pyridin-2-ylmethyl-
amine ;
<IMG>
[3-(4-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-pyridin-2-ylmethyl-amine ;
<IMG>
[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-pyridin-2-ylmethyl-
amine ;
<IMG>
4-[6-(3-Chloro-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-2-methoxy-phenol ;

- 235 -
<IMG>
{4-[6-(3-Chloro-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-methanol
<IMG>
(3-Chloro-benzyl)-[3-(5-methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine;
<IMG>
3-[6-(3-Chloro-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenol
<IMG>
(3-Chloro-benzyl)-(3-pyridin-3-yl-imidazo[1,2-b]pyridazin-6-yl)-amine;
<IMG>
[3-(3-Amino-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(3-chloro-benzyl)-amine;

- 236 -
<IMG>
(3-Chloro-benzyl)-[3-(6-methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine
<IMG>
4-[6-(3-Chloro-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenol;
<IMG>
(3-Chloro-benzyl)-(3-pyridin-4-yl-imidazo[1,2-b]pyridazin-6-yl)-amine;
<IMG>
3-[6-(3-Chloro-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzamide
<IMG>
4-[6-(3-Chloro-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzoic acid ;

- 237 -
<IMG>
(4-Fluoro-benzyl)-(3-pyridin-4-yl-imidazo[1,2-b]pyridazin-6-yl)-amine
<IMG>
4-[6-(4-Fluoro-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenol;
<IMG>
(4-Fluoro-benzyl)-[3-(5-methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine
<IMG>
3-[6-(4-Fluoro-benzylamino)-imidazo[1,2-b]pyridazin-3-yI]-phenol;
<IMG>
(4-Fluoro-benzyl)-[3-(4-methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine

- 238 -
<IMG>
(3-Benzo[1,3]dioxol-5-yl-imidazo[1,2-b]pyridazin-6-yl)-(4-fluoro-benzyl)-
amine;
<IMG>
(4-Fluoro-benzyl)-[3-(1H-indol-5-yl)-imidazo[1,2-b]pyridazin-6-yl]-amine;
<IMG>
(4-Fluoro-benzyl)-[3-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-amine;
<IMG>
(4-Fluoro-benzyl)-[3-(6-methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl)-
amine;
<IMG>
N-{3-[6-(4-Fluoro-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
acetamide;

- 239 -
<IMG>
(4-Fluoro-benzyl)-(3-pyridin-3-yl-imidazo[1,2-b]pyridazin-6-yl)-amine
<IMG>
{4-[6-(4-Fluoro-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}methanol;
<IMG>
3-[6-(4-Fluoro-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzamide
<IMG>
4-[6-(4-Fluoro-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzoic acid
<IMG>
(4-Methoxy-benzyl)-(3-p-tolyl-imidazo[1,2-b]pyridazin-6-yl)-amine

- 240 -
<IMG>
[3-(4-Chloro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(4-methoxy-benzyl)-amine
<IMG>
(4-Methoxy-benzyl)-[3-(4-methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
[3-(1H-Indol-5-yl)-imidazo[1,2-b]pyridazin-6-yl]-(4-methoxy-benzyl)-amine
<IMG>
(4-Methoxy-benzyl)-[3-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-amine
<IMG>
[3-(4-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(4-methoxy-benzyl)-amine

-241-
<IMG>
4-[6-(4-Methoxy-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenol ;
<IMG>
(4-Methoxy-benzyl)-[3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl)-amine ;
<IMG>
(4-Methoxy-benzyl)-[3-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
4-[6-(4-Methoxy-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzoic acid ;
<IMG>
4-{[3-(3,4,5-Trimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-methyl}-
benzenesulfonamide ;

-242-
<IMG>
4-{[3-(4-Hydroxy-3-methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-methyl}-
benzenesulfonamide ;
<IMG>
4-{(3-(3-Hydroxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-methyl}-
benzenesulfonamide ;
<IMG>
4-[(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-ylamino)-methyl]-
benzenesulfonamide ;
<IMG>
4-[(3-p-Tolyl-imidazo[1,2-b]pyridazin-6-ylamino)-methyl]-benzenesulfonamide ;
<IMG>
4-{[3-(3,4-Dimethyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-methyl}-
benzenesulfonamide ;

- 243 -
<IMG>
4-{[3-(4-Cyano-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-methyl)-
benzenesulfonamide
<IMG>
4-{[3-(3-Trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylaminol-methyl)-
benzenesulfonamide 1
<IMG>
4-{(3-(1H-Indol-5-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-methyl}-
benzenesulfonamide ;
<IMG>
4-[(3-Benzo[1,31dioxo1-5-yl-imidazo[1,2-b]pyridazin-6-ylamino)-methyl]-
benzenesulfonamide;
<IMG>
4-{[3-(3-Chloro-4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-methyl}-
benzenesulfonamide;

- 244 -
<IMG>
4-{[3-(3-Trifluoromethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-methyl}-
benzenesulfonamide ,
<IMG>
4-{[3-(4-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-methyl}-
benzenesulfonamide ,
<IMG>
4-{[3-(4-Hydroxy-phenyI)-imidazo[1,
2-b]-pyridazin-6-ylamino]-methyl)-be
Nzenesulfonamide,
<IMG>
4-{[3-(3-Hydroxymethyl-phenyl)-imid
azo[1,2-b]pyridazin-6-ylamino]-meth
yl}-benzenesulfonamide ,
<IMG>
4-{[3-(3-Acetyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-methyl}-
benzenesulfonamide ;

- 245 -
<IMG>
4-{[3-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1 ,2-b]pyridazin-6-ylamino]-methyl)-
benzenesulfonamide
<IMG>
(3,4-Dichloro-benzyl)-[3-(3,4,5-trimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-
yl]-amine
<IMG>
4-[6-(3,4-Dichloro-benzylamino)-imidazo[1 ,2-b]pyridazin-3-yl)-phenol,
<IMG>
(3,4-Dichloro-benzyl)-[3-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-
amine
<IMG>
(3,4-Dichloro-benzyl)-[3-(6-methoxy-pyridin-3-0)--imidazo[1,2-b]pyridazin-6-
yl]-amine ;

- 246 -
<IMG>
(3,4-Dichloro-benzyl)-[3-(1H-indol-5-yl)-imidazo[1,2-b]pyridazin-6-yl)-amine ;
<IMG>
4-[6-(3,4-Dichloro-benzylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzoic acid ;
<IMG>
Benzo[1,3]dioxol-5-ylmethyl-(3-pyridin-4-yl-imidazo[1,2-b]pyridazin-6-yl)-
amine ;
<IMG>
4-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-2-
methoxy-phenol ;
<IMG>
Benzo[1,3]dioxol-5-ylmethyl-[3-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-
yl]-amine ;
<IMG>
Benzo[1,3]dioxol-5-ylmethyl-[3-(6-methoxy-pyridin-3-yl)-imidazo[1,2-
b)pyridazin-6-yl)-amine ,

- 247 -
<IMG>
4-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl)-
phenol
<IMG>
3-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-
phenol
<IMG>
Benzo[1,3]dioxol-5-ylmethyl-[3-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-
b]pyridazin-6-yl)-amine
<IMG>
4-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-
benzoic acid
<IMG>
N-(3-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl)-
phenyI)-
methanesulfonamide ;
<IMG>
3-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-imidazo[1,2-b]pyridazin-3-yl}-
benzamide;

-248-
<IMG>
(2-Methoxy-ethyl)-[3-(3,4,5-trimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
(2-Methoxy-ethyl)-[3-(3-methoxy-phenyl)imidazo[1,2-b]pyridazin-6-yl]-amine ;
<IMG>
2-Methoxy-4-[6-(2-methoxy-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenol ;
<IMG>
(2-Methoxy-ethyl)-[3-(5-methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
(2-Methoxy-ethyl)-(3-naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-amine ;
<IMG>
(2-Methoxy-ethyl)-[3-(6-methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;

-249-
<IMG>
(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-(2-methoxy-ethyl)-amine
;
<IMG>
[3-(4-Chloro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(2-methoxy-ethyl)-amine ;
<IMG>
(2-Methoxy-ethyl)-(3-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl)-amine ;
<IMG>
(3-Benzo[1,3]dioxol-5-yl-imidazo[1,2-b]pyridazin-6-yl)-(2-methoxy-ethyl)-amine
;
<IMG>
(2-Methoxy-ethyl)-[3-(3-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
N-{3-[6-(2-Methoxy-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-acetamide
;

-250-
<IMG>
(2-Methoxy-ethyl)-[3-(3-trifluoromethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
[3-(1H-Indol-5-yl)-imidazo[1,2-b]pyridazin-6-yl]-(2-methoxy-ethyl)-amine ;
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(2-methoxy-ethyl)-amine ;
<IMG>
(2-Methoxy-ethyl)-[3-(4-methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
4-[6-(2-Methoxy-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenol ;
<IMG>
{4-[6-(2-Methoxy-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-methanol ;

-251-
<IMG>
(2-Methoxy-ethyl)-[3-(3-methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl}-amine ;
<IMG>
[3-(3-Bromo-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(2-methoxy-ethyl)-amine ;
<IMG>
4-[6-(2-Methoxy-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzoic acid ;
<IMG>
3-[6-(2-Methoxy-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzamide ;
<IMG>
N-{3-[6-(2-Methoxy-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
methanesulfonamide ;
<IMG>
[3-(1-Benzyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-(2-methoxy-ethyl)-
amine ;

-252-
<IMG>
[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2b]pyridazin-6-yl]-(2-methoxy-ethyl)-amine
;
<IMG>
1-{3-[6-(2-Methoxy-ethylamino)-imidazo[1,2-b]pyridazin-3-yl)-phenyl}-ethanone
;
<IMG>
3-[3-(3,4,5-Trimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-propan-1-ol
;
<IMG>
4-[6-(3-Hydroxy-propylamino)-imidazo[1,2-b]pyridazin-3-yl]-2-methoxy-phenol ;
<IMG>
3-[3-(3-Bromo-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-propan-1-ol ;
<IMG>
3-[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-propan-1-ol ;

-253-
<IMG>
3-[3-(3-Trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-propan-1-
ol,
<IMG>
3-[3-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-propan-1-ol
;
<IMG>
3-[3-(3-Trifluoromethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-propan-1-
ol ;
<IMG>
3-[3-(4-Methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-propan-1-ol ;
<IMG>
3-(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-ylamino)-propan-1-ol ;
<IMG>
3-(3-p-Tolyl-imidazo[1,2-b]pyridazin-6-ylamino)-propan-1-ol ;

- 254 -
<IMG>
3-(3-Thiophen-3-yl-imidazo[1,2-b]pyridazin-6-ylamino)-propan-1-ol; ;
<IMG>
3-(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-ylamino)-propan-1-ol ;
<IMG>
3-[3-(6-Methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-propan-1-ol;
;
<IMG>
3-[3-(1H-Indol-5-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-propan-1-ol;
<IMG>
3-[3-(4-Methoxy-phenyI)-imidazo[1,2-b]pyridazin-6-ylamino]-propan-1-ol ;
<IMG>
3-[3-(3-Chloro-4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-ylaminol-propan-1-
ol;

-255-
<IMG>
3-[3-(3-Chloro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-propan-1-ol ;
<IMG>
N-{3-[6-(3-Hydroxy-propylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
methanesulfonamide ;
<IMG>
3-[3-(1-Benzyl-1H-pyrazol-4-yl)-imidazo[1,2-b]-pyridazin-6-ylamino]-propan-1-
ol ;
<IMG>
3-[3-(3-Dimethylamino-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-propan-1-ol ;
<IMG>
3-(3-Naphthalen-1-yl-imidazo[1,2-b]pyridazin-6-ylamino)-propan-1-ol ;
<IMG>
Propyl-[3-(3,4,5-trimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-amine ;

- 256 -
<IMG>
2-Methoxy-4-(6-propylamino-imidazo[1,2-b]pyridazin-3-yl)-phenol ;
<IMG>
[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-propyl-amine ;
<IMG>
[3-(1H-Indol-5-yl)-imidazo[1,2-b]pyridazin-6-yl)-propyl-amine
<IMG>
[3-(3-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl)-propyl-amine ;
<IMG>
N-[3-(6-Propylamino-imidazo[1,2-b]pyridazin-3-yl)-phenyl)-acetamide ;
<IMG>
Propyl-[3-(3-trifluoromethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-amine

-257-
<IMG>
[3-(4-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl-propyl-amine ;
<IMG>
Propyl-(3-thiophen-3-yl-imidazo[1,2-b]pyridazin-6-yl)-amine ;
<IMG>
[3-(4-Methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-yl]-propyl-amine ;
<IMG>
Propyl-(3-pyridin-3-yl-imidazo[1,2-b]pyridazin-6-yl)-amine ;
<IMG>
[3-(6-Methoxy-pyridin-3-yl)-imidazo
[1,2-b]pyridazin-6-yl]-propyl-amine ;
<IMG>
4-(6-Propylamino-imidazo[1,2-b]pyridazin-3-yl)-phenol ;

-258-
<IMG>
(3-Benzo[1,3]dioxol-5-yl-imidazo[1,2-b]pyridazin-6-yl)-propyl-amine ;
<IMG>
[3-(6-Propylamino-imidazo[1,2-b]pyridazin-3-yl)-phenyl]-methanol ;
<IMG>
4-(6-Propylamino-imidazo[1,2-b]pyridazin-3-yl)-benzoic acid ;
<IMG>
3-(6-Propylamino-imidazo[1,2-b]pyridazin-3-yl)-benzamide ;
<IMG>
[3-(3-Dimethylamino-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-propyl-amine ;
<IMG>
3-(6-Propylamino-imidazo[1,2-b]pyridazin-3-yl)-phenol ;

-259-
<IMG>
(3-(3-Amino-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-propyl-amine ;
<IMG>
[3-(4-Amino-phenyl-imidazo[1,2-b]pyridazin-6-yl]-propyl-amine ;
<IMG>
[3-(4-Dimethylamino-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-propyl-amine
<IMG>
[4-(6-Propylamino-imidazo[1,2-b]pyridazin-3-yl)-phenyl]-methanol ;
<IMG>
[3-(5-Methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-propyl-amine;
<IMG>
N,N-Dimethyl-N'-(3-p-tolyl-imidazo[1,2-b]pyridazin-6-yl)-ethane-1,2-diamine ;

-260-
<IMG>
N'-(3-Benzofuran-2-yl-imidazo[1,2-b]pyridazin-6-yl)-N,N-dimethyl-ethane-1,2-
diamine ;
<IMG>
N,N-Dimethyl-N'-(3-thiophen-3-yl-imidazo[1,2-b]pyridazin-6-yl)-ethane-1,2-
diamine ;
<IMG>
N,N-Dimethyl-N'-(3-naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-ethane-1,2-
diamine ;
<IMG>
N'-(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-N,N-dimethyl-ethane-
1,2-diamine ;
<IMG>
N'-[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-N,N-dimethyl-ethane-
1,2-diamine ;
<IMG>
N'-[3-(4-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-N,N-dimethyl-ethane-1,2-
diamine ;

-261-
<IMG>
N'-[3-(3-Chloro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-N,N-dimethyl-ethane-1,2-
diamine ;
<IMG>
(S)-3-Methyl-2-[3-(3,4,5-trimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-
butan-1-ol ;
<IMG>
4-[6-((S)-1-Hydroxymethyl-2-methyl-propylamino)-imidazo[1,2-b]pyridazin-3-yl]-
2-methoxy-
phenol ;
<IMG>
(S)-2-[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-3-methyl-
butan-1-ol ;
<IMG>
3-[6-((S)-1-Hydroxymethyl-2-methyl-propylamino)-imidazo[1,2-b]pyridazin-3-yl]-
phenol ;
<IMG>
4-[6-((S)-1-Hydroxymethyl-2-methyl-propylamino)-imidazo[1,2-b]pyridazin-3-yl]-
phenol ;

-262-
<IMG>
(S)-2-[3-(4-Hydroxymethyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-3-methyl-
butan-1-ol ;
<IMG>
(S)-2-[3-(3-Dimethylamino-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-3-methyl-
butan-1-ol ;
<IMG>
(S)-3-Methyl-2-(3-naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-ylamino)-butan-1-
ol ;
<IMG>
(S)-3-Methyl-2-[3-(3-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazin-6-
ylamino]-butan-1-ol ;
<IMG>
(S)-2-(3-Benzo[1,3]dioxol-5-yl-imidazo[1,2-b]pyridazin-6-ylamino)-3-methyl-
butan-1-ol ;
<IMG>
(S)-3-Methyl-2-[3-(4-methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-
butan-1-ol ;

- 263 -
<IMG>
(S)-3-Methyl-2-(3-thiophen-3-yl-imidazo[1,2-b]pyridazin-6-ylamino)-butan-1-ol
<IMG>
(S)-3-Methyl-2-[3(3-trifluoromethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-
ylamino]-butan-1-ol
<IMG>
(S)-2-[3(3-Chloro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-3-methyl-butan-1-
ol
<IMG>
(S)-2-[3(4-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-3-methyl-butan-1-
ol;
<IMG>
(S)-2-[3(1H-Indol-5-yl )-imidazo[1,2-b]pyridazin-6-ylamino]-3-methyl-butan-1-
ol ;
<IMG>
3-[6-((S)-1-Hydroxymethyl-2-methyl-propylamino)-imidazo[1,2-b]pyridazin-3-yl]-
benzamide

-264-
<IMG>
1-{3-[6-((S)-1-Hydroxymethyl-2-methyl-propylamino)-imidazo[1,2-b]pyridazin-3-
yl]-phenyl}-
ethanone ;
<IMG>
(S)-2-[3-(5-Methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-3-methyl-
butan-1-ol ;
<IMG>
2-[3-(3,4,5-Trimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol ;
<IMG>
2-[3-(3-Chloro-4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol
;
<IMG>
2-(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-ylamino)-butan-1-ol ;
<IMG>
2-[3-(3-Trifluoromethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol
;

-265-
<IMG>
2-(3-Thiophen-3-yl-imidazo[1,2-b]pyridazin-6-ylamino)-butan-1-ol ;
<IMG>
2-[3-(4-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol ;
<IMG>
2-[3-(4-Methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol ;
<IMG>
2-[3-(3-Chloro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol ;
<IMG>
2-[3-(6-Methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol ;
<IMG>
2-[3-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol
;

-266-
<IMG>
2-[3-(3-Bromo-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol ;
<IMG>
2-[3-(3-Trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol
;
<IMG>
2-[3-(3-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol ;
<IMG>
3-[6-(1-Hydroxymethyl-propylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzamide ;
<IMG>
4-[6-(1-Hydroxymethyl-propylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzoic acid
;
<IMG>
2-[3-(1-Benzyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol
;

-267-
<IMG>
N-{3-[6-(1-Hydroxymethyl-propylamino)-Imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
methanesulfonamide ;
<IMG>
1-{3-[6-(1-Hydroxymethyl-propylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
ethanone
<IMG>
2-[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol
<IMG>
2-[3-(5-Methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-butan-1-ol ,
<IMG>
(Tetrahydro-pyran-4-yl)-(3-(3,4,5-trimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-
yl]-amine ,
<IMG>
[3-(3-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-
amine

-268-
<IMG>
(Tetrahydro-pyran-4-yl)-[3-(3-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazin-
6-yl]amine ;
<IMG>
{4-[6-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
methanol ;
<IMG>
[3-(4-Methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-
yl)-amine ;
<IMG>
[3-(3-Chloro-4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-
4-yl)-amine ;
<IMG>
[3-(3-Bromo-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-
amine ;
<IMG>
[3-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-
4-yl)-amine ;

- 269 -
<IMG>
[3-[6-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl)-
methanol ;
<IMG>
[3-(5-Methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-
yl)-amine i
<IMG>
[3-(4-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-
amine 7
<IMG>
[3-(4-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-
amine ;
<IMG>
[3-(1H-Indo1-5-yl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-amine
;
<IMG>
[3-(3-Dimethylamino-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-
yl)-amine ;

-270-
<IMG>
(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-(tetrahydro-pyran-4-yl)-amine
;
<IMG>
[3-(3,4-Dimethyl-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-
amine,;
<IMG>
(3-Furan-2-yl-imidazo[1,2-b]pyridazin-6-yl)-(tetrahydro-pyran-4-yl)-amine
<IMG>
N-(2-Hydroxy-ethyl)-3-[6-(tetrahydra-pyran-4-ylamino)-imidazo[1,2-b]pyridazin-
3-yl]-benzamide
<IMG>
4-[6-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzoic acid
methyl ester ;
<IMG>
(Tetrahydro-pyran-4-yl)-(3-p-tolyl-imidazo[1,2-b]pyridazin-6-yl)-amine

- 271 -
<IMG>
[3-(4-Amino-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-
amine
<IMG>
[3-[4-Dimethylamino-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-
yl)-amine
<IMG>
N-{3-[6-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
acetamide
<IMG>
[3-(3-Amino-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-
amine
<IMG>
[3-(2-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-
amine
<IMG>
(3-Naphthalen-1-yl-imidazo[1,2-b]pyridazin-6-yl)-(tetrahydro-pyran-4-yl)-amine

-272-
<IMG>
(3-Pyridin-3-yl-imidazo[1,2-b]pyridazin-6-yl)-(tetrahydro-pyran-4-yl)-amine ;
<IMG>
[3-(4-Chloro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-
amine ;
<IMG>
(3-Benzo[1,3]dioxol-5-yl-imidazo[1,2-b]pyridazin-6-yl)-(tetrahydro-pyran-4-yl)-
amine ;
<IMG>
3-[6-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenol ;
<IMG>
(Tetrahydro-pyran-4-yl)-(3-thiophen-3-yl-imidazo[1,2-b]pyridazin-6-yl)-amine ;
<IMG>
[3-(3,4-Dimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-
yl)-amine ;

-273-
<IMG>
(Tetrahydro-pyran-4-yl)-[3-(3-trifluoromethoxy-phenyl)-imidazo[1,2-b[pyridazin-
6-yl]-amine;
<IMG>
[3-(3-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-
amine;
<IMG>
2-memory-4-[6-(tetrahydro-pyran-4-ylamino)-imidazo[1,2-b]pyridazin-3-yl]-
phenol;
<IMG>
(Tetrahydro-pyran-4-yl)-(3-thiophen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-amine;
<IMG>
(3-(1H-Pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-
amine;
<IMG>
3-[6-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzamide;

-274-
<IMG>
[3-(1-Benzyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-
4-yl)-amine;
<IMG>
4-[6-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzoic acid ;
<IMG>
N-{3-[6-(Tretrahydro-pyran-4-ylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
methanesulfonamide ;
<IMG>
[3-(3-Chloro-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-
amine ;
<IMG>
4-[6-(4-Hydroxy-cyclohexylamino)-imidazo[1,2-b]pyridazin-3-yI]-2-methoxy-
phenol;

-275-
<IMG>
4-[3-(3-Trifluoromethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-
cyclohexanol ;
<IMG>
4-[3-(3-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-cyclohexanol;
<IMG>
4-(3-Thiophen-3-yl-imidazo[1,2-b]pyridazin-6-ylamino)-cyclohexanol;
<IMG>
4-(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-ylamino)-cyclohexanol;
<IMG>
4-[3-(3-Dimethylamino-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-cyclohexanol;
<IMG>
4-[3-(3-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-cyclohexanol ;

-276-
<IMG>
4-(3-Naphthalen-1-yl-imidazo[1,2-b]pyridazin-6-ylamino)-cyclohexanol;
<IMG>
N-{3-[6-(4-Hydroxy-cyclohexylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
acetamide;
<IMG>
4-[6-(4-Hydroxy-cyclohexylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenol;
<IMG>
4-(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-ylamino)-cyclohexanol;
<IMG>
4-(3-Phenyl-imidazo[1,2-b]pyridazin-6-ylamino)-cyclohexanol;
<IMG>
4-[3-(1H-Indol-5-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-cyclohexanol;

-277-
<IMG>
4-[3-(4-Dimethylamino-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-cyclohexanol;
<IMG>
4-[3-(4-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-cyclohexanol;
<IMG>
4-(3-Quinolin-8-yl-imidazo[1,2-b]pyridazin-6-ylamino)-cyclohexanol;
<IMG>
4-(3-Furan-2-yl-imidazo[1,2-b]pyridazin-6-ylamino)-cyclohexanol;
<IMG>
4-[6-(4-Hydroxy-cyclohexylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzoic acid
methyl ester;
<IMG>
4-[3-(4-Trifluoromethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-
cyclohexanol;

-278-
<IMG>
4-[3-(3,4-Dimethyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-cyclohexanol;
<IMG>
4-[3-(4-Hydroxymethyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-cyclohexanol;
<IMG>
4-[3-(4-Chloro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-cyclohexanol;
<IMG>
4-[3-(6-Methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-ylamino]cyclohexanol;
<IMG>
4-[3-(5-Methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-cyclohexanol
;
<IMG>
3-[6-(4-Hydroxy-cyclohexylamino)-imidazo[1,2-b]pyridazin-3-yl]-phenol;

-279-
<IMG>
4-[6-(4-Hydroxy-cyclohexylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzoic acid ;
<IMG>
Cyclopropylmethyl-[3-(3,4,5-trimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
4-[6-(Cyclopropylmethyl-amino)imidazo[1,2-b]pyridazin-3-yl]-2-methoxy-phenol ;
<IMG>
Cyclopropylmethyl-[3-(3,4-dimethoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-
amine
<IMG>
Cyclopropylmethyl-[3-(3-dimethylamino-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
Cyclopropylmethyl-(3-pyridin-4-yl-imidazo[1,2-b]pyridazin-6-yl)-amine

-280-
<IMG>
{3-(6-(Cyclopropylmethyl-amino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}methanol
;
<IMG>
Cyclopropylmethyl-[3-(3-methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-amine ;
<IMG>
Cyclopropylmethyl-[3-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
Cyclopropylmethyl-[3-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-amine ;
<IMG>
(3-Benzo[1,3]dioxol-5-yl-imidazo[1,2-b]pyridazin-6-yl)-cyclopropylmethyl-amine
;
<IMG>
Cyclopropylmethyl-[3-(4-methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-amine ;

-281-
<IMG>
Cyclopropylmethyl-(3-thiophen-3-yl-imidazo[1,2-b]pyridazin-6-yl)-amine ;
<IMG>
Cyclopropylmethyl-[3-(6-methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
Cyclopropylmethyl-[3-(4-methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-yl]-
amine ;
<IMG>
N-{3-[6-(Cyclopropylmethyl-amino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
acetamide ;
<IMG>
3-[6-(Cyclopropylmethyl-amino)-imidazo[1,2-b]pyridazin-3-yl]-N-(2-hydroxy-
ethyl)-benzamide ;
<IMG>
(4-[6-(Cyclopropylmethyl-amino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-methanol
;

-282-
<IMG>
4-[6-(Cyclopropylmethyl-amino)-imidazo[1,2-b]pyridazin-3-yl]-phenol ;
<IMG>
3-[6-(Cyclopropylmethyl-amino)-imidazo[1,2-b]pyridazin-3-yl]-phenol ;
<IMG>
N-{3-[6-(Cyclopropylmethyl-amino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
methanesulfonamide ;
<IMG>
3-[6-(Cyclopropylmethyl-amino)-imidazo[1,2-b]pyridazin-3-yl]-benzoic acid ;
<IMG>
[3-(1-Benzyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-cyclopropylmethyl-
amine ;
<IMG>
4-[6-(Cyclopropylmethyl-amino)-imidazo[1,2-b]pyridazin-3-yl]-benzoic acid ;

-283-
<IMG>
3-[6-(Cyclopropylmethyl-amino)-imidazo[1,2-b]pyridazin-3-yl]-benzamide ;
<IMG>
1-{3-[6-(Cyclopropylmethyl-amino)-imidazo[1,2-b]pyridazin-3-yl]-phenyl}-
ethanone ;
<IMG>
Cyclopropylmethyl-(3-thiophen-2-yl-imidazo[1,2-b]pyridazin-6-yl)-amine ;
[3-(2-Methoxy-pyridin-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-piperidin-4-yl-amine
;
4-[3-(2-Methoxy-pyridin-4-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-piperidine-1-
carboxylic
acid tert-butyl ester ;
<IMG>
(3-(6-Methoxy-pyridin-3-yl)-imidazo[1,2-b]pyridazin-6-yl]-piperidin-4-yl-amine
;
3-[6-(2-Hydroxy-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-benzenesulfonamide ;

-284-
<IMG>
4-[6-(2-Hydroxy-ethylamino)-imidazo
[1,2-b]pyridazin-3-yl)-benzenesulfo
Namide ;
<IMG>
4-[6-(3-Dimethylamino-propylamino)-
imidazo[1,2-b]pyridazin-3-yl]-phenol ;
or
<IMG>
4-[6-(2-Morpholin-4-yl-ethylamino)-
imidazo[1,2-b]pyridazin-3-yl]-phenol.

-285-
11. An intermediate according to formula IIa
<IMG>
wherein
Y is a halogen atom, and
R1 and R2 are each as defined in claim 1.
12. An intermediate according to formula lIb
<IMG>
wherein
Q, A and B are each as defined in claim 1, and
X is chlorine, bromine, O-SO2-CF3 or O-SO2-C4F9;
with the proviso that the intermediate is not

- 286 -
<IMG>
13. A method for preparing a compound as defined in any one of claims 1 to 10,
comprising the following steps:
A1) converting 3-amino-6-halopyrazine into 6-haloimidazo[1,2-b]pyridazine II,
A2) converting the product from stage A1 into a 3-halo-6-haloimidazo[1,2-
b]pyridazine III,
A3) converting the product from stage A2 by reaction with a compound NHR1R2
into a
compound according to formula Ila as defined in claim 11, and
A4) converting the product from stage A3 into the compound as defined in any
one of
claims 1 to 10,
or
B1) converting 3-amino-6-halopyrazine into 6-haloimidazo[1,2-b]pyridazine II,
B2) converting the product from stage B1 into a 3-halo-6-haloimidazo[1,2-
b]pyridazine III,
B3) converting the product from stage B2 into a compound according to formula
lIb as
defined in claim 12, and
B4) converting the product from stage B3 into the compoundas defined in any
one of
claims 1 to 10,
or
C1) converting 3-amino-6-halopyrazine into 6-haloimidazo[1,2-b]pyridazine II,
C2) converting the product from stage C1 by reaction with a compound NHR1R2
into an
imidazo[1,2-b]pyridazin-6-yl)-(R1)-(R2)-amine IV,
C3) converting the product from stage C2 into the compound according to
formula Ila,
and

-287-
C4) converting the product from stage C3 into the compoundas defined in any
one of
claims 1 to 10.
14. The method as claimed in claim 11, comprising the following steps:
A1) reacting 3-amino-6-halopyrazine with chloractetaldehyde to give 6-
haloimidazo[1,2-
b]pyridazine,
A2) reacting the product from stage A1 with N-bromosuccinimide to give a 3-
bromo-6-
haloimidazo[1,2-b]pyridazine,
A3) converting the product from stage A2 by reaction with a compound NHR1R2 in
a
Buchwald-Hartwig cross-coupling reaction into a (3-bromoimidazo[1,2-
b]pyridazin-
6-yl)-(R1)-(R2)-amine, and
A4) reacting the product from stage A3 with a boronic acid which is optionally
substituted
by the radicals A and B to give the compound as defined in any one of claims 1
to
10,
or
B1) reacting 3-amino-6-halopyrazine with chloractetaldehyde to give 6-
haloimidazo[1,2-
b]pyridazine,
B2) reacting the product from stage B1 with N-bromosuccinimide to give a 3-
bromo-6-
haloimidazo[1,2-b]pyridazine,
B3) reacting the product from stage B2 with a boronic acid which is optionally
substituted
by the radicals A and B to give the compound according to formula IIb, and
B4) converting the product from stage B3 by reacting with a compound NHR1R2 in
a
Buchwald-Hartwig cross-coupling reaction into the compound as defined in any
one
of claims 1 to 10,
or
C1) reacting 3-amino-6-halopyrazine with chloractetaldehyde to give 6-
haloimidazo[1,2-
b]pyridazine,

- 288 -
C2) converting the product from stage C1 by reacting with a compound NHR1R2 in
a
Buchwald-Hartwig cross-coupling reaction into an imidazo[1,2-b]pyridazin-6-yl)-
(R1)-(R2)-amine,
C3) reacting the product from stage C2 with N-bromosuccinimide to give a
(3-bromoimidazo[1,2-b]pyridazin-6-yl)-(R1)-(R2)-amine, and
C4) reacting the product from stage C3 with a boronic acid which is optionally
substituted
by the radicals A and B to give the compound as defined in any one of claims 1
to
10.
15. Use of a compound as defined in any one of claims 1 to 10 in the
manufacture of a
medicament for treating a disorder associated with over-expression of a
cellular
kinase.
16. Use of a compound as defined in any one of claims 1 to 10 in the
manufacture of a
medicament for inhibiting a cellular kinase.
17. The use as claimed in claim 15 to 16, wherein the kinase belongs to the
group of the
protein kinase C family.
18. The use as claimed in claim 17, wherein the kinase is PKC theta, delta,
iota, alpha
or zeta.
19. The useas claimed in claim 15 or 16, wherein the kinase is from the class
of the ALK
family.
20. The use as claimed in claim 19, wherein the kinase is ALK1, ALK2, ALK4 or
ALK5.
21. The use as claimed in claim 15, wherein the disorder is a benign tumor, a
malignant
tumor leukemia, lymphoma, sarcoma, neuroblastoma, a Wilm's tumor, a malignant
neoplasm of the bladder, breast, lung, pancreas, prostate, or kidney, or a
neoplasm
of epithelial origin.
22. The use as claimed in claim 15, wherein the disorder is an epidermal
hyperproliferation, Alzheimer's disease, an autoinflammatory disorder,
fibroses,
impaired wound healing, diabetic retinopathy, nephropathy, age-related macular
degeneration, Crohn's disease, exaggerated immune response, contact
dermatitis,
atopic dermatitis, multiple sclerosis, ALS, diabetes, or asthma.

- 289 -
23. A pharmaceutical composition comprising a compound as defined in any one
of
claims 1 to 10, and a pharmaceutically acceptable carrier, for treating a
disorder
associated with over-expression of a cellular kinase.
24. The pharmaceutical composition as claimed in claim 23, wherein the
disorder is a
benign tumor, a malignant tumor leukemia, lymphoma, sarcoma, neuroblastoma, a
Wilm's tumor, a malignant neoplasm of the bladder, breast, lung, pancreas,
prostate, or kidney, or a neoplasm of epithelial origin.
25. The pharmaceutical composition as claimed in claim 23, wherein the
disorder is an
epidermal hyperproliferation, Alzheimer's disease, an autoinflammatory
disorder,
fibroses, impaired wound healing, diabetic retinopathy, nephropathy, age-
related
macular degeneration, Crohn's disease, exaggerated immune response, contact
dermatitis, atopic dermatitis, multiple sclerosis, ALS, diabetes, or asthma.

Description

CA 02620534 2008-02-28
SRG/US/53343 - 1-
ALJ/TDS
Substituted imidazo[1,2131pyridazines
as kinase inhibitors, their preparation
=
and use as medicaments
The present invention relates to novel substituted imidazo[1,2b]pyridazines,
their
preparation and use as medicament for the treatment of various disorders.
The compounds described in this invention are suitable for inhibiting kinases,
preferably kinases of the protein kinase (PK) family and, in this connection,
to especially for inhibiting kinases of the PKC subfamily, very
particularly for inhibiting
the PKC theta kinase. The present compounds are suitable as kinase inhibitors
for
the treatment of a large number of disorders which are attributable to a
dysfunction
of a kinase, including immunological and general inflammatory processes, and
oncological processes, but also disorders such as, for example, type II
diabetes
is and asthma, and transplants; preferably inflammatory processes and
immune
= responses which exhibit the clinical appearance of acute dermatitis, of
contact
dermatitis but also of psoriasis.
A single publication (Bioorg. Med. Chem. Lett. 2004, 14, 2249-2252.) discloses
pyrimidine derivatives with an attached imidazo[1,2b]pyridazine residue as
kinase
20 inhibitors. These compounds differ from the compounds of the invention
through
their structure, in particular on the imidazo[1,2b]pyridazine ring. The patent
application WO 02/066481 (AstraZeneca) describes pyridazine-substituted
pyrimidines as antiproliferative substances. Further prior art is mentioned
hereinafter.

CA 02620534 2008-02-28
.SRG/US/53343 - 2 -
ALJ/TDS
There is a continuing great need for effective medicaments for the treatment
of
immunological and also cell-proliferative disorders, in particular in
dermatological
indications.
It has now been found that substituted imidazo[1,2b]pyridazines of the general
formula I in which
R1,
N N
R2 0 A
Formula I
to where
is aryl or heteroaryl ¨ with the exception of pyrimidine;
A and B are identical or different and are selected from the group consisting
of
i) H, Hal, -OH, -NR3R4, -CN, or -NO2,
ii) optionally mono- or poly-Hal-, -OH-, C3-C6-heterocycloalkyl-, -NR3R4-,
-SO2NR3R4- , -S02R3- or -(C0)-NR3-L-substituted Cl-C6-alkyl, Cl -C6-
haloalkyl, Cl-C6-alkoxy, Cl-C6-haloalkoxy, C3-C6-cycloalkyl or C3-C6-
heterocycloalkyl, where the C3-C6-heterocycloalkyl may comprise in the
ring optionally one or more nitrogen, oxygen and/or sulfur atoms and/or
=
one or more -(CO)- or -(SO2)- groups and/or one or more double bonds,
and
iii) -NR3(C0)-L, -NR3(C0)-NR3-L, -(C0)-R6, -0-(CH2)p-R6,
-(C0)-(NR3)-L, -NR3(CS)-NR3R4, -NR3(S02)-L, -(S02)-NR3R4,
-NR3(CO)NR3R4, -(CO)NR3R4, -0O2R7, -NR3(S02)R4 or -0-(CH2)p-aryl,
where the substituents in the case of polysubstitution may be identical or
different,
A and B in addition to the aforementioned definition together form a 0-fused
C5-C7-cycloalkyl or C5-C7-heterocycloalkyl ring, where the latter

CA 02620534 2008-02-28
SRG/US/53343 - 3-
ALJ/TDS
comprises at least one oxygen or one nitrogen atom in the ring, and may
optionally comprise additionally in the ring one or more oxygen, nitrogen
or sulfur atoms and/or one or more -(CO)- or -(SO2)- groups and/or
optionally one or more double bonds,
p is 0 to 4,
is optionally mono- or poly-hydroxy-, C1-C6-alkyl-, C1-C6-haloalkyl-, C1-C6-
haloalkyl-, C1-C6-hydroxyalkoxy-, C1-C6-alkoxy-, C1-C6-haloalkoxy-,
C1-C6-alkoxyalkoxy-, C3-C6-heterocycloalkyl-, or -NR3R4-substituted C1-
C6-alkyl, C1-C6-haloalkyl or C3-C6-cycloalkyl or C3-C6-heterocycloalkyl,
io where the C3-C6 heterocycloalkyl may comprise in the ring optionally
one or
more nitrogen, oxygen and/or sulfur atoms and/or one or more -(CO)- or
-(SO2)- groups and/or one or more double bonds;
R1 and R2 are identical or different and are selected from the group
consisting of
j) -H and
jj) optionally mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-haloalkyl-,
C1-C6-alkoxy-, C1-C6-haloalkoxy-, C1-C6-hydroxyalkyl-, C3-C6-cycloalkyl-,
C3-C6-heterocycloalkyl-, C2-C6-alkynyl-, aryl-, aryloxy-, heteroaryl-, -S-C1-
C6-alkyl-, -(C0)-R8-, -NR3R4-, -NR3(C0)-L-, -NR3COOR7-, -COOR7-,
-NR3CONR3R4-, -NR3S02R4-, -SO2NR3R4- , -CONR3R4- or -SO2R3-
substituted C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy,
C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl,
aryl or heteroaryl or
with -(CH2)rR8 radical, where r is a number 0-3, and R8 is a radical
H
0 11 or
0/K-F

CA 02620534 2008-02-28
SRG/US/53343 - 4-
ALJ/TDS
where aryl, heteroaryl, C3-C6-cycloalkyl or C3-C6-heterocycloalkyl groups
optionally present in R1 or R2 may be substituted one or more times by -Hal,
-CN, - OH, -C1-C6-alkyl, C1-C6-haloalkyl, -C1-C6-alkoxy, C1-C6-haloalkoxy,
-C1-C6-hydroxyalkyl, -C3-C6-cycloalkyl, -NO2, -N H2, -C1-C6-haloalkyl,
-NR3R4, -CONR3R4, -NR3COR4, NR3S02R4, -COR6, CO2R7, -SO2NR3R4,
-SR3, SOR3, -S02R3, -0R3, -0(CH2)pR6, where the substituents in the case of
polysubstitution may be identical or different;
where two or more aryl or heteroaryl groups may not be substituents on
the same carbon atom in R1 or R2;
po R1 and R2 in addition to the aforementioned definition may together form
a
C3-C6-heterocycloalkyl ring which comprises at least one nitrogen
atom in the ring and may optionally comprise additionally in the ring
one or more nitrogen, oxygen or sulfur atoms and/or one or more
-(C0)- or -(SO2)- groups and/or optionally one or more double bonds,
where the ring formed by R1 and R2 may be optionally substituted one
or more times by -CN, -Hal, -OH, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-
cycloalkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxyalkyl, C1-C6-haloalkoxy-,
Cl -C6-haloalkoxyalkyl, -NR3R4, -CONR6R7, -(C0)-R6 or -COOR7 and/or
by optionally mono- or poly-Hal-, C1-C6-alkoxy-, C1-C6-haloalkoxy- or
-(C0)-R6-substituted aryl or heteroaryl, where the substituents in the
case of polysubstitution may be identical or different;
R3 and R4 are identical or different and are selected from the group
consisting of
j) -H, and jj) optionally mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-
haloalkyl-, C1-C6-alkoxy-, C1-C6-haloalkoxy-, C1-C6-hydroxyalkyl-, C3-C6-
cycloalkyl-, C3-C6 heterocycloalkyl-, C2-C6-alkynyl-, aryl-, aryloxy-,
heteroaryl-, -NR6R7-, -CONR6R7-, -(C0)-R6- or -COOR7-substituted
C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-
alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or
heteroaryl, where the C3-C6-heterocycloalkyl may comprise in the ring
optionally one or more nitrogen, oxygen and/or sulfur atoms and/or one or

CA 02620534 2008-02-28
SRG/US/53343 - 5 -
ALJ/TDS
more -(CO)- or -SO2- groups and/or one or more double bonds, and
where the substituents in the case of polysubstitution may be identical or
different;
R3 and R4 in addition to the aforementioned definition may together form a
C3-C6-heterocycloalkyl ring which comprises at least one nitrogen
atom in the ring and may optionally comprise additionally in the ring
one or more nitrogen, oxygen or sulfur atoms and/or one or more
-(CO)- or ¨(SO2)- groups and/or optionally one or more double bonds,
where the ring formed by R3 and R4 may be optionally substituted one
or more times by -CN, -Hal, -OH, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-
cycloalkyl, Cl -C6-hydroxyalkyl, Cl -C6-haloalkoxy, Cl -C6-
haloalkoxyalkyl, C1-C6-alkoxyalkyl, or by -NR6R7, -CONR6R7, -(C0)-R6
or -COOR7 and/or by optionally mono- or poly-Hal-, C1-C6-alkoxy-, C1-
C6-haloalkoxy- or -(C0)-R6-substituted aryl or heteroaryl, where the
substituents in the case of polysubstitution may be identical or
different;
R6 and R7 are identical or different and are selected from the group
consisting of
j) -H and jj) optionally mono- or poly-Hal-, -OH-, -CN- substituted C1-C6-
alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl,
C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl,
where the C3-C6-heterocycloalkyl may comprise in the ring optionally one
or more nitrogen, oxygen and/or sulfur atoms and/or one or more -(CO)-
or -SO2- groups and/or one or more double bonds, and where the
substituents in the case of polysubstitution may be identical or different,
and the isomers, diastereomers, enantiomers and salts thereof, represent
effective
compounds for inhibiting kinases (defined hereinafter) and therefore can be
employed for a number of disorders (defined hereinafter).

CA 02620534 2008-02-28
SRG/US/53343 - 6 -
ALJ/TDS
Alkyl means in each case a straight-chain or branched alkyl radical such as,
for
example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
butyl,
pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl.
Alkoxy means in each case a straight-chain or branched alkoxy radical such as,
for
example, methyloxy, ethyloxy, propyloxy, isoproplyloxy, butyloxy, isobutyloxy,
sec
butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or
decyloxy.
The alkenyl substituents are in each case straight-chain or branched, with the
following radicals being meant for example: vinyl, propen-1-yl, propen-2-yl,
but-1-
en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methylprop-2-en-1-yl,
2-
methylprop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl, ally!.
Alkynyl means in each case a straight-chain or branched alkynyl radical which
comprises 2-6, preferably 2-4, C atoms. Examples of suitable radicals are the
following: ethynyl, propyn-1-yl, propyn-3-y1 (propargyl), but-1-yn-1-yl, but-1-
yn-4-yl,
is but-2-yn-1-yl, but-1-yn-3-yl, 3-nnethylbut-1-yn-3-yl.
C1-C6-Haloalkyl stands for a straight-chain or branched alkyl radical in which
at
least one hydrogen atom is replaced by a halogen atom (fluorine, chlorine,
bromine
or iodine, preferably fluorine or chlorine), such as, for example
fluoromethyl,
trichloromethyl, 1,2-difluoroethyl, perfluoropropyl, 3,3,3-trifluoropropyl,
1-fluoroisopropyl, perfluorobutyl, etc. Perfluoromethyl and perfluoroethyl
groups are
very particularly preferred.
C1-C6-Haloalkoxy stands for a straight-chain or branched alkoxy radical in
which
at least one hydrogen atom is replaced by a halogen atom (fluorine, chlorine,
bromine or iodine, preferably fluorine or chlorine), such as, for example,
fluoromethoxy, trichloromethoxy, 1,2-difluoroethoxy, perfluoropropoxy, 3,3,3-
trifluoropropoxy, 1-fluoroisopropoxy, perfluorobutoxy, etc. Perfluoromethoxy
and
perfluoroethoxy groups are very particularly preferred.

CA 02620534 2008-02-28
SRG/US/53343 -7 -
ALJ/TDS
C3-C6-Heterocycloalkyl stands for an alkyl ring including 3-6 carbon atoms,
where
the heterocycloalkyl comprises in the ring at least one atom, identical or
different,
from the following group oxygen, sulfur or nitrogen, and may optionally be
interrupted by one or more -(CO)-, -(CS)- or -SO2- groups in the ring, and may
optionally comprise one or more double bonds in the ring, and the ring itself
may
optionally be substituted one or more times, identically or differently.
Examples of heterocycloalkyl which may be mentioned are: oxiranyl, oxethanyl,
dioxolanyl, dithianyl, dioxanyl, aziridinyl, azetidinyl, tetrahydrofuranyl,
tetrahydropyranyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl,
tetrahydroisoquinolinyl, octahydroisoquinolinyl, tetrahydroquinolinyl,
octahydroquinolinyl, tetrahydroimidazolonyl, pyrazolidinyl, pyrrolidinyl,
pyrrolidonyl,
piperidinyl, piperidonyl, piperazinyl, piperazinonyl, N-methylpyrolidinyl, 2-
hydroxy-
methylpyrolidinyl, 3-hydroxypyrolidinyl, N-methylpiperazinyl, N-
benzylpiperazinyl,
N-acetylpiperazinyl, N-methylsulfonylpiperazinyl, 4-hydroxypiperidinyl, 4-
amino-
carbonylpiperidinyl, 2-hydroxyethylpiperidinyl, 4-hydroxymethylpiperidinyl,
imidazolidinyl, tetrahydroimidazolonyl, nnorpholinyl, thiomorpholinyl, 1,1-
dioxothio-
morpholinyl, trithianyl, tetrahydrotriazinthionyl, triazinthionyl,
quinuclidinyl,
nortropinyl, pydridonyl.
Preferred heterocycloalkyl groups which may be mentioned are:
tetrahydropyranyl,
pyrrolidinyl, piperidinyl, N-methylpiperidinyl, piperazinonyl, N-
methylpiperazinyl,
morpholinyl, pyrridonyl.
Substituents on the heterocycloalkyl ring may be for example: cyano, halogen,
hydroxy, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-
alkoxyalkyl, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, aryl or optionally
identically or
differently mono- or poly-halogen-, hydroxyl- or C1-C6-alkylthio-substituted
C1-C6-
alkyl, C1-C6-haloalkyl or a substituent from the group ¨(C0)-C1-C6-alkyl,
¨(CO)-O-
C1 -C6-alkyl, ¨(S02)-phenyl, -NH2, -N(Ci-C6-alky1)2, -NH(C1-
C6-
alkyl) etc.

CA 02620534 2008-02-28
SRG/US/53343 - 8 -
ALJ/TDS
Cycloalkyl means monocyclic alkyl rings such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl, but also bicyclic rings or tricyclic
rings such
as, for example, adamantanyl. The cycloalkyl may also optionally be benzo-
fused,
such as, for example, (tetralin)yl etc.
Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
Halogen means in each case fluorine, chlorine, bromine or iodine.
The aryl radical in Q and the aryl radical optionally present in R1 and R2
includes in
each case 3-12 carbon atoms and may in each case be benzo-fused. Examples
which may be mentioned are: cyclopropenyl, cyclopentadienyl, phenyl, tropyl,
cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl,
anthracenyl,
tetralinyl etc.
The heteroaryl radical Q includes in each case 5-16 ring atoms and may
comprise
in place of the carbon one or more identical or different heteroatoms such as
oxygen, nitrogen or sulfur in the ring, and may be mono-, bi- or tricyclic,
and may
is additionally be in each case benzo-fused. Pyrinnidine is not included as
group Q in
the definition of heteroaryl.
Examples which may be mentioned are: thienyl, furanyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
triazolyl,
thiadiazolyl, etc. and benzo derivatives thereof, such as, for example,
benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl,
isoindolyl, etc.; or pyridyl, pyridazinyl, pyrazinyl, triazinyl, etc. and
benzo derivatives
thereof, such as, for example, quinolyl, isoquinolyl, etc.; or oxepinyl,
azocinyl,
indolizinyl, indolyl, indolinyl, isoindolyl, indazolyl, benzimidazolyl,
purinyl, etc. and
benzo derivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl,
phthalazinyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, tetralinyl, etc.
Preferred heteroaryl radicals are for example 5-membered heteroaromatic rings
such as thienyl, furanyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl and benzo

CA 02620534 2008-02-28
SRG/US/53343 - 9 -
ALJ/IDS
derivatives of the 5-membered heteroaromatic rings, and 6-membered
heteroaromatic rings, such as pyridinyl, triazinyl, and benzo derivatives of
the 5-
membered heteroaromatic rings, such as quinolinyl, isoquinolinyl.
The heteroaryl radical optionally present in R1 or R2 includes in each case 5-
16 ring
atoms and may comprise instead of the carbon one or more identical or
different
heteroatoms such as oxygen, nitrogen or sulfur in the ring, and may be mono-,
bi-
or tricyclic, and may additionally in each case be benzo-fused.
Examples of the heteroaryl radical in R1 or R2 which may be mentioned are:
thienyl, furanyl, pyrroidinylyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,
isoxazolyl,
to isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and benzo
derivatives thereof,
such as, for example, benzofuranyl, benzothienyl, benzoxazolyl,
benzimidazolyl,
indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl,
triazinyl, etc. and benzo derivatives thereof, such as, for example, quinolyl,
isoquinolyl, etc.; or oxepinyl, azocinyl, indolizinyl, indolyl, indolinyl,
isoindolyl,
is indazolyl, benzimidazolyl, purinyl, etc. and benzo derivatives thereof;
or quinolinyl,
isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
naphthyridinyl,
pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
xanthenyl, tetralinyl, etc.
Examples of preferred heteroaryl radicals in R1 or R2 are 5-membered
20 heteroaromatic rings such as thienyl, pyrazolyl, furanyl, oxazolyl,
thiazolyl, triazolyl,
imidazolyl and benzo derivatives thereof and 6-membered heteroaromatic rings
such as pyridinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl and benzo
derivatives
thereof.
Particularly preferred heteroaryl radicals in R1 or R2 are thienyl, pyrazolyl,
furanyl,
25 oxazolyl, thiazolyl, triazolyl, imidazolyl, pyridinyl, pyrazinyl,
triazinyl, quinolinyl,
isoquinolinyl.
If a plurality of aryl or heteroaryl groups are present in R1 or R2, two or
more aryl or
heteroaryl groups may not be substituents on the same carbon atom.

CA 02620534 2008-02-28
SRG/US/53343 -10-
ALJ/TDS
Thus, for example, a group
C,51-1
-CH
1
C6H5
is precluded as group R1 or R2.
Should aryl, heteroaryl, C3-C6-cycloalkyl or C3-C6-heterocycloalkyl groups be
present in R1 or R2, these may be substituted one or more times by -Hal, -CN, -
OH,
-Cl -C6-alkyl, Cl -C6-haloalkyl, -Cl -C6-alkoxy, Cl -C6-haloalkoxy, -Cl -C6-
hydroxyalkyl, -C3-C6-cycloalkyl, -NO2, -NH2, -C1-C6-haloalkyl, -NR3R4, -
CONR3R4,
-NR3COR4, NR3S02R4, -COR6, CO2R7, -SO2NR3R4, -SR3, SOR3, --S02R3, -0R3,
-0(CH2)pR6, where the substituents in the case of polysubstitution may be
identical
or different. In a preferred embodiment, the aryl, heteroaryl, C3-C6-
cycloalkyl or
C3-C6-heterocycloalkyl groups present in R1 or R2 have not more than 3 of the
abovementioned substituents.
Isomers mean chemical compounds of the same molecular formula but different
is chemical structure. A distinction is made in general between
constitutional isomers
and stereoisomers.
Constitutional isomers have the same molecular formula but differ through the
manner of attachment of their atoms or atomic groups. These include functional
isomers, positional isomers, tautomers or valence isomers.
Stereoisomers have in principle the same structure (constitution) ¨ and thus
also
the same molecular formula ¨ but differ through the spatial arrangement of the
atoms.
A distinction is made in general between configurational isomers and
conformational isomers. Configurational isomers are stereoisomers which can be
converted into one another only by breaking a bond. These include enantiomers,
diastereomers and E/Z (cis/trans) isomers.

CA 02620534 2008-02-28
SRG/US/53343 - 11 -
ALJ/TDS
Enantiomers are stereoisomers which are related to one another as image and
mirror image and have no plane of symmetry. All stereoisomers which are not
enantiomers are referred to as diastereomers. E/Z (cis/trans) isomers at
double
bonds are a special case.
Conformational isomers are stereoisomers which can be converted into one
another by rotation of single bonds.
See also the IUPAC rules section E (Pure App!. Chem. 1976, 45, 11-30.)
concerning the categorization of the type of isomerism.
The compounds of the invention of the general formula I also encompass the
to possible tautomeric forms and include the E or Z isomers or, if a chiral
center is
present, also the racemates and enantiomers. Double-bond isomers are also to
be
understood thereby.
The compounds of the invention may also exist in the form of solvates, in
particular
of hydrates, in which case the compounds according to the invention
accordingly
comprise polar solvents, in particular water, as structural element of the
crystal
lattice of the compounds according to the invention. The proportion of polar
solvent, in particular water, may be in a stoichiometric or else non-
stoichiometric
ratio. Terms used in connection with stoichiometric solvates, hydrates are
also
hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or
hydrates.
If an acidic function is present, suitable salts are the physiologically
tolerated salts
of organic and inorganic bases such as, for example, the readily soluble
alkali
metal and alkaline earth metal salts, and salts of N-methylglucamine,
dimethylglucamine, ethylglucamine, lysine, 1,6-hexanediamine, ethanolamine,
glucosamine, sarcosine, serinol, trishydroxymethylaminomethane,
aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.
If a basic function is present, the physiologically tolerated salts of organic
and
inorganic acids are suitable, such as hydrochloric acid, sulfuric acid,
phosphoric
acid, citric acid, tartaric acid, fumaric acid, maleic acid, malic acid and
others.

CA 02620534 2008-02-28
SRG/US/53343 - 12 -
ALJ/TDS
Preferred compounds of the general formula I are those compounds in which R1
and R2 are identical or different and are selected from the group consisting
of
j) -H and jj) optionally mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-
haloalkyl-, C1-C6-alkoxy-, C1-C6-haloalkoxy-, C1-C6-hydroxyalkyl-, C3-C6-
cycloalkyl-, C3-C6 heterocycloalkyl-, C2-C6-alkynyl-, aryl-, aryloxy-,
heteroaryl-,
-S-C1-C6-alkyl-, -(C0)-R6-, -NR3R4-, -NR3(C0)-L-, or -NR3COOR7-substituted
C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl,
C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, where the C3-C6-
heterocycloalkyl may optionally comprise in the ring one or more nitrogen,
oxygen
io and/or sulfur atoms and/or one or more -(CO)- or -SO2- groups and/or one
or
more double bonds, and where the substituents in the case of polysubstitution
may be identical or different. Q, A, B, R3, R4, R6, R7, p and L may in this
case be
varied as defined above.
Further preferred compounds of the general formula I are those in which R1 and
R2
is are identical or different and are selected from the group consisting of
j) -H and
jj) optionally mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-haloalkyl-,
C1-C6-
alkoxy-, C1-C6-haloalkoxy-, C1-C6-hydroxyalkyl-, C3-C6-cycloalkyl-, C3-C6
heterocycloalkyl-, C2-C6-alkynyl-, aryloxy-, -S-C1-C6-alkyl-, -(C0)-R6-, -
NR3R4-,
-NR3(C0)-L-, or -NR3COOR7-substituted C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-
alkoxy,
20 Cl -C6-haloalkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-
heterocycloalkyl, aryl or heteroaryl, where the C3-C6-heterocycloalkyl may
optionally
comprise in the ring one or more nitrogen, oxygen and/or sulfur atoms and/or
one
or more -(CO)- or -SO2- groups and/or one or more double bonds, where the
group aryl or heteroaryl defined in jj) may be substituted as long as alkyl is
not
25 involved, and where the substituents in the case of polysubstitution may
be
identical or different. Q, A, B, R3, R4, R6, R7, p and L may in this case be
varied
as defined above.
Further preferred compounds of the general formula I are those in which Q is:
-OH-, -Hal-, -CN-, alkyl-, -0R6-, or -NR3R4-substituted phenyl, pyridyl,
thiophenyl,
30 furyl, imidazolyl or pyrazolyl, where R1 and R2 are identical or
different and are

CA 02620534 2008-02-28
SRG/US/53343 - 13-
ALJ/TDS
selected from the group consisting of j) -H and jj) optionally mono- or poly-
Hal-, -OH-,
-CN-, C1-C6-alkyl-, C1-C6-haloalkyl-, C1-C6-alkoxy-, C1-C6-haloalkoxy-, C1-C6-
hydroxyalkyl-, C3-C6-cycloalkyl-, C3-C6 heterocycloalkyl-, C2-C6-alkynyl-,
aryloxy-,
-S-C1-C6-alkyl-, -(C0)-R6-, -NR3R4-, -NR3(C0)-L- or -NR3COOR7-substituted C1-
C6-
alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-
alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl, where
the
C3-C6-heterocycloalkyl may optionally comprise in the ring one or more
nitrogen,
oxygen and/or sulfur atoms and/or one or more -(CO)- or -SO2- groups and/or
one
or more double bonds, where the group aryl or heteroaryl defined in jj) may be
io substituted as long as alkyl is not involved, and where the substituents
in the case
of polysubstitution may be identical or different. R3, R4, R6, R7, p and L may
in this
case be varied as defined above.
Further preferred compounds of the general formula I are those in which R1 and
R2 are identical or different and are selected from the group consisting of -
H,
NR3R4-substituted C1-C4 alkyl, optionally additionally mono- or poly-Hal-, -OH-
, -CN-,
C1-C6-alkyl-, C1-C6-haloalkyl-, C1-C6-alkoxy-, C1-C6-haloalkoxy-, C1-C6-
hydroxyalkyl-, C3-C6-cycloalkyl-, C3-C6 heterocycloalkyl-, C2-C6-alkynyl-,
aryl-,
aryloxy-, heteroaryl-, -S-C1-C6-alkyl-, -(C0)-R6-, -NR3(C0)-L- or -NR3COOR7-
substituted, optionally mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-
haloalkyl-,
C1-C6-alkoxy-, C1-C6-haloalkoxy-, C1-C6-hydroxyalkyl-, C3-C6-cycloalkyl-, C3-
C6
heterocycloalkyl-, C2-C6-alkynyl-, aryl-, aryloxy-, heteroaryl-,
-(C0)-R6-, -NR3(C0)-L-, -NR3R4- or -NR3COOR7-substituted C5-C6-cycloalkyl, C5-
C6-
heterocycloalkyl, where R3 and R4 may optionally be identically or differently
C1-C6-alkyl, C1-C6-haloalkyl, where R3 and R4 may together form a C3-C6-
heterocycloalkyl ring which comprises at least one nitrogen atom in the ring
and
may optionally additionally comprise in the ring one or more nitrogen, oxygen
or
sulfur atoms and/or one or more -(C0)- or -(SO2)- groups and/or optionally one
or more double bonds, and where R6 and R7 is identically or differently -H, -
OH,
C1-C6-alkoxy, C1-C6-haloalkoxy, or C1-C3 alkyl.

CA 02620534 2008-02-28
SRG/US/53343 - 14-
ALJ/TDS
Particularly preferred compounds of the general formula I are those in which
R1 is
selected from the group consisting of ¨H and C1-C3-alkyl, where R2 is selected
from the group consisting of NR3R4-substituted C3-C4 alkyl, optionally
additionally
mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-haloalkyl-, C1-C6-alkoxy-,
C1-C6-haloalkoxy-, C1-C6-hydroxyalkyl-, C3-C6-cycloalkyl-, C3-C6
heterocycloalkyl-,
C2-C6-alkynyl-, aryl-, aryloxy-, heteroaryl-, -S-C1-C6-alkyl-, -(C0)-R6-, -
NR3(C0)-L- or
-NR3COOR7-substituted, where R3 and R4 are identically or differently
optionally
mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-haloalkyl-, C1-C6-alkoxy-,
C1-C6-haloalkoxy-, C1-C6-hydroxyalkyl-, C3-C6-cycloalkyl-, C3-C6
heterocycloalkyl-,
C2-C6-alkynyl-, aryl-, aryloxy-, heteroaryl-, -NR6R7-, -CONR6R7-, -(C0)-R6- or
-COOR7-substituted C1-C6-alkyl, C1-C6-haloalkyl, where R3 and R4 may together
form a C3-C6-heterocycloalkyl ring which comprises at least one nitrogen atom
in
the ring and may optionally additionally comprise in the ring one or more
nitrogen,
oxygen or sulfur atoms and/or one or more -(C0)- or -(SO2)- groups and/or
optionally one or more double bonds, and where R6 and R7 is identically or
differently -H, -OH, C1-C6-alkoxy, C1-C6-haloalkoxy, or C1-C3 alkyl.
In a further preferred embodiment, R1 or R2 is a hydrogen atom.
The following compounds mentioned in the examples are particularly preferred:
= 2.0 ¨ 2.21
= 3.0 ¨ 3.80
= 4.0 ¨ 4.11
= 5.0 ¨ 5.389
= 6.0 ¨ 6.2
= 7.0 ¨ 7.1
= 8.0 ¨ 8.1
A further aspect of the present invention is represented by a compound of the
general formula ha and the use thereof for preparing a compound according to
formula I, in which

CA 02620534 2008-02-28
SRG/US/53343 -15-
ALYTDS
R1, NfN r:Ni
,N
R2
General formula ha
is a halogen atom (preferably chlorine or bromine),
R1 and R2 are identical or different and selected from the group consisting of
j) ¨H and
jj) optionally mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-haloalkyl-,
C1-C6-alkoxy-, C1-C6-haloalkoxy-, C1-C6-hydroxyalkyl-, C3-C6-cycloalkyl-,
C3-C6 heterocycloalkyl-, C2-C6-alkynyl-, aryl-, aryloxy-, heteroaryl-, -S-C1-
C6-alkyl-, -(C0)-R6-, -NR3R4-, -NR3(C0)-L- or -NR3COOR7-substituted
C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-
alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or
heteroaryl, where the C3-C6-heterocycloalkyl may optionally comprise in
the ring one or more nitrogen, oxygen and/or sulfur atoms and/or one or
more -(CO)- or -SO2- groups and/or one or more double bonds, and
where the substituents in the case of polysubstitution may be identical or
different;
R1 and R2 in addition to the preceding definition may together form a C3-C6-
heterocycloalkyl ring which comprises at least one nitrogen atom in the
ring and may optionally additionally comprise in the ring one or more
nitrogen, oxygen or sulfur atoms and/or one or more -(CO)- or -(S02)-
groups and/or optionally one or more double bonds, where the ring
formed via R1 and R2 may be optionally substituted one or more times
by -CN, -Hal, -OH, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl,
C1-C6-hydroxyalkyl, C1-C6-haloalkoxyalkyl, C1-C6-haloalkoxy, C1-C6-
alkoxyalkyl, -NR3R4, -CONR6R7, -(C0)-R6 or -COOR7 and/or by
optionally mono- or poly-Hal-, C1-C6-alkoxy-, C1-C6-haloalkoxy- or

CA 02620534 2008-02-28
SRG/US/53343 - 16 -
ALJ/TDS
-(C0)-R6-substituted aryl or heteroaryl, where the substituents in the
case of polysubstitution may be identical or different;
where three or more nitrogen atoms in the ring may not be linked directly
to one another;
where aryl, heteroaryl, C3-C6-cycloalkyl or C3-C6-heterocycloalkyl
groups optionally present in R1 or R2 may be substituted one or more
times by -Hal, -CN, - OH, -C1-C6-alkyl, C1-C6-haloalkyl, -C1-C6-alkoxy,
C1-C6-haloalkoxy, -C1-C6-hydroxyalkyl, -C3-C6-cycloalkyl, -NO2, -NH2,
-C1-C6-haloalkyl, -NR3R4, -CONR3R4, -NR3COR4, NR3S02R4, -COR6,
CO2R7, -SO2NR3R4, -SR3, SOR3, --SO2R3, -0R3, -0(CH2)pR6, where the
substituents in the case of polysubstitution may be identical or different;
R3 and R4 are identical or different and selected from the group consisting of
j)-H
and jj) optionally mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-
haloalkyl-, C1-C6-alkoxy-, C1-C6-haloalkoxy-, C1-C6-hydroxyalkyl-, C3-C6-
cycloalkyl-, C3-C6 heterocycloalkyl-, C2-C6-alkynyl-, aryl-, aryloxy-,
heteroaryl-, -NR6R7-, -CONR6R7-, -(C0)-R6- or -COOR7-substituted
C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-
alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or
heteroaryl, where the C3-C6-heterocycloalkyl may optionally comprise in
the ring one or more nitrogen, oxygen and/or sulfur atoms and/or one or
more -(CO)- or -SO2- groups and/or one or more double bonds, and
where the substituents in the case of polysubstitution may be identical or
different;
R3 and R4 in addition to the preceding definition may together form a C3-C6-
heterocycloalkyl ring which comprises at least one nitrogen atom in the
ring and may optionally additionally comprise in the ring one or more
nitrogen, oxygen or sulfur atoms and/or one or more -(CO)- or -(SO2)-
groups and/or optionally one or more double bonds, where the ring
formed by R3 and R4 may optionally be substituted one or more times
by -CN, -Hal, -OH, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl,

CA 02620534 2008-02-28
SRG/US/53343 - 17 -
ALJ/TDS
Cl-C6-hydroxya I kyl, C1-C6-alkoxyalkyl C1-C6-haloalkoxyalkyl, C1-C6-
haloalkyl or -NR6R7, -CONR6R7, -(C0)-R6 or -COOR7 and/or by
optionally mono- or poly-Hal-, C1-C6-alkoxy-, C1-C6-haloalkoxy- or
-(C0)-R6-substituted aryl or heteroaryl, where the substituents in the
case of polysubstitution may be identical or different;
R6 and R7 are identical or different and selected from the group consisting of
j)¨H
and jj) optionally mono- or poly-Hal-, -OH-, -CN-substituted C1-C6-alkyl,
C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-
er5,N
X N
0 A
alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl, where
the C3-C6-heterocycloalkyl may optionallyt comprise in the ring one or
more nitrogen, oxygen and/or sulfur atoms and/or one or more -(CO)- or
-SO2- groups and/or one or more double bonds, and where the
substituents in the case of polysubstitution may be identical or different,
and the isomers, diastereomers, enantiomers and salts thereof.
is A further aspect of the present invention is represented by a compound
of the
general formula lib and the use thereof for preparing a compound according to
formula I, in which
general formula lib
X is chlorine, bromine, 0-S02-CF3 or 0-S02-C4F9;
Q is aryl or heteroaryl ¨ with the exception of pyrimidine;
A and B are identical or different and selected from the group consisting of
i) H,
Hal, -OH, -NR3R4, -CN or -NO2,

CA 02620534 2008-02-28
SRG/US/53343 - 18 -
ALJ/TDS
ii) optionally mono- or poly-Hal-, -OH-, C3-C6-heterocycloalkyl-, -NR3R4-,
-SO2NR3R4-, -S02R3- or -(C0)-NR3-L-substituted C1-C6-alkyl, C1-C6-
haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C6-cycloalkyl or C3-C6-
heterocycloalkyl, where the C3-C6-heterocycloalkyl may optionally
comprise in the ring one or more nitrogen, oxygen and/or sulfur atoms
and/or one or more -(CO)- or -(SO2)- groups and/or one or more double
bonds, and
iii) -NR3(C0)-L, -NR3(C0)-NR3-L, -(C0)-R6, -0-(CH2)p-R6,
-(C0)-(NR3)-L, -NR3(CS)-NR3R4, -NR3(S02)-L, -(S02)-NR3R4,
-NR3(CO)NR3R4, -(CO)NR3R4, -CO2R7, -NR3(S02)NR4 or -0-(CH2)p-aryl,
where the substituents in the case of polysubstitution may be identical or
different,
A and B in addition to the preceding definition together form a Q-fused C5-C7-
cycloalkyl or C5-C7-heterocycloalkyl ring, where the latter comprises at
least one oxygen or nitrogen atom in the ring and may optionally
additionally comprise in the ring one or more oxygen, nitrogen or sulfur
atoms and/or one or more -(C0)- or -(SO2)- groups and/or optionally
one or more double bonds,
isOto4,
L is optionally mono- or poly-hydroxy-, C1-C6-alkyl-, C1-C6-haloalkyl-,
C1-C6-hydroxyalkoxy-, C1-C6-alkoxy-, C1-C6-haloalkoxy-, C1-C6-
alkoxyalkoxy-, C3-C6-heterocycloalkyl- or -NR3R4-substituted C1-C6-alkyl,
C1-C6-haloalkyl or C3-C6-cycloalkyl or C3-C6-heterocycloalkyl, where the
C3-C6 heterocycloalkyl may optionally comprise in the ring one or more
nitrogen, oxygen and/or sulfur atoms and/or one or more -(C0)- or -(SO2)-
groups and/or one or more double bonds;
R3 and R4 are identical or different and selected from the group consisting of
j) -H,
and jj) optionally mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-
haloalkyl-, C1-C6-alkoxy-, C1-C6-haloalkoxy-, C1-C6-hydroxyalkyl-, C3-C6-

CA 02620534 2008-02-28
SRG/US/53343 - 19 -
ALJ/TDS
cycloalkyl-, C3-C6 heterocycloalkyl-, C2-C6-alkynyl-, aryl-, aryloxy-,
heteroaryl-, -NR6R7-, -CONR6R7-, -(C0)-R6- or -COOR7-substituted
C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-
alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or
heteroaryl, where the C3-C6-heterocycloalkyl may optionally comprise in
the ring one or more nitrogen, oxygen and/or sulfur atoms and/or one
more -(CO)- or -SO2- groups and/or one or more double bonds, and
where the substituents in the case of polysubstitution may be identical or
different;
lo R3 and R4 may in addition to the preceding definition together form a C3-
C6-
heterocycloalkyl ring which comprises at least one nitrogen atom in the
ring and may optionally additionally comprise in the ring one or more
nitrogen, oxygen or sulfur atoms and/or one or more -(CO)- or -(SO2)-
groups and/or optionally one or more double bonds, where the ring
formed via R3 and R4 may optionally be substituted one or more times
by -CN, -Hal, -OH, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl,
Cl -C6-hydroxyalkyl, Cl -C6-alkoxyalkyl, Cl -C6-haloalkoxyalkyl,
C1-C6-haloalkoxy or by -NR6R7, -CONR6R7, -(C0)-R6 or -COOR7
and/or by optionally mono- or poly-Hal-, C1-C6-alkoxy-, C1-C6-
haloalkoxy- or -(C0)-R6-substituted aryl or heteroaryl, where the
substituents may in the case of polysubstitution be identical or
different;
R6 and R7 are identical or different and selected from the group consisting of
j)¨H
and jj) optionally mono- or poly-Hal-, -OH-, -CN-substituted C1-C6-alkyl,
C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-
alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl, where
the C3-C6-heterocycloalkyl may optionally comprise in the ring one or
more nitrogen, oxygen and/or sulfur atoms and/or one or more -(CO)- or
-SO2- groups and/or one or more double bonds, and where the
substituents in the case of polysubstitution may be identical or different

CA 02620534 2008-02-28
SRG/US/53343 - 20 -
ALJ/TDS
and the isomers, diastereomers, enantiomers and salts thereof.
These compounds of the general formulae ha and lib represent advantageous
intermediates and can be employed in the synthesis of the abovennentioned
compounds of the general formula I.
The explanations made above for the compounds of the formula I, including the
preferred embodiments of the radicals, apply in principle analogously to the
compounds of the formulae Ila and Ilb. It is particularly preferred for 0 to
be an
optionally mono- or poly-OH-, -Hal-, -ON-, alkyl-, -0R6- or -NR3R4-substituted
phenyl, pyridyl, thiophenyl, furyl, imidazolyl or pyrazolyl. It is further
preferred for X
to be ¨CI or ¨Br.
The following intermediates of the invention are particularly preferred: 3-
bromo-6-
chloroimidazo[1,2-b]pyridazines, imidazo[1,2-b]pyridazin-6-y1-(3-pyrrolidin-1-
ylpropyl)amines, 6-chloro-3-phenylimidazo[1,2-b]pyridazines, 6-chloro-3-(3-
chlorophenyl)imidazo[1,2-13]pyridazines, 6-chloro-3-(1 -methyl-1 H-pyrazol-4-
yl)imidazo[1,2-b]pyridazines, 6-chloro-3-thiophen-3-ylimidazo[1,2-
b]pyridazines.
The intermediates 1.0-1.28 described in the examples are very particularly
preferred.

CA 02620534 2008-02-28
SRG/US/53343 - 21 -
ALSTDS
Synthesis scheme:
A N/_
X N
AL A
1117 V
General formula Ilb
NH ey-14
2
N N
X N X N X N
III 42 0 A
B
VII
General formula I
R1, 121, A -1;1-.?
N N
N N A2 Y
VI
IV
General formula ha
The invention accordingly also relates to a method for preparing a compound of
the
invention with the following stages of the method:
Al) 3-amino-6-halopyrazine is converted into 6-haloimidazo[1,2-b]pyridazine
II,
A2) the product from stage Al is converted into a 3-halo-6-haloimidazo[1,2-
b]pyridazine III,
A3) the product from stage A2 is converted by reaction with a compound NHR1R2
io into the compound according to the general formula Ila,
A4) the product from stage A3 is converted into the compound according to the
general formula I,
or
B1) 3-amino-6-halopyrazine is converted into 6-haloimidazo[1,2-b]pyridazine
II,
is B2) the product from stage B1 is converted into a 3-halo-6-
haloimidazo[1,2-
b]pyridazine III,

CA 02620534 2008-02-28
SRG/US/53343 -22-
ALJ/TDS
=
B3) the product from stage B2 is converted into the compound according to the
general formula lib,
B4) the product from stage B3 is converted into the compound according to the
general formula I,
or
Cl) 3-amino-6-halopyrazine is converted into 6-haloimidazo[1,2-14yridazine II,
CZ) the product from stage Cl is converted by reaction with a compound NHR1R2
into an imidazo[1,2-b]pyridazin-6-yI)-(R1)-(R2)-amine IV,
C3) the product from stage C2 is converted into the compound according to the
general formula Ila,
C4) the product from stage 03 is converted into the compound according to the
general formula I.
Said reactions are preferably carried out as follows:
is Al) 3-amino-6-halopyrazine is reacted with chloractetaldehyde to give 6-
haloimidazo[1,2-b]pyridazine,
A2) the product from stage Al is reacted with N-bromosuccinimide to give a 3-
bromo-6-haloimidazo[l ,2-b]pyridazine,
A3) the product from stage A2 is converted by reaction with a compound NHR1 R2
in a Buchwald-Hartwig cross-coupling reaction into a (3-bromoimidazo[1,2-
b]pyridazin-6-yI)-(R1)-(R2)-amine,
A4) the product from stage A3 is reacted for example with a boronic acid which
is
optionally substituted by the radicals A and B to give the compound
according to the general formula I,

CA 02620534 2008-02-28
SRG/US/53343 - 23 -
ALJ/TDS
or
B1) 3-amino-6-halopyrazine is reacted with chloractetaldehyde to give 6-
haloimidazo[1,2-b]pyridazine,
B2) the product from stage B1 is reacted with N-bromosuccinimide to give a 3-
bromo-6-haloimidazo[1,2-b]pyridazine,
B3) the product from stage B2 is reacted for example with a boronic acid which
is
optionally substituted by the radicals A and B to give the compound
according to the general formula II,
B4) the product from stage B3 is converted by reacting with a compound NHR1R2
io in a Buchwald-Hartwig cross-coupling reaction into the compound
according
to the general formula I,
or
Cl) 3-amino-6-halopyrazine is reacted with chloractetaldehyde to give 6-
haloimidazo[1,2-b]pyridazine,
in a Buchwald-Hartwig cross-coupling reaction into an imidazo[1,2-
b]pyridazin-6-y1)-(R1)-(R2)-amine,
C3) the product from stage C2 is reacted with N-bromosuccinimide to give a (3-
bromoimidazo[1,2-b]pyridazin-6-yI)-(R1)-(R2)-amine,
optionally substituted by the radicals A and B to give the compound
according to the general formula I.
The compounds of the invention are particularly preferably prepared by
synthesis
route Al-A4.

CA 02620534 2008-02-28
SRG/US/53343 - 24-
ALJ/TDS
To protect sensitive side groups, said synthesis routes can also be prepared
with
use of protective groups. Such protective group techniques are known to the
skilled worker, e.g. from T.W. Greene, P.G.M. Wuts õProtective Groups in
Organic Synthesis", 2nd edition, John Wiley and Sons, 1991.
Stages Al, B1 and Cl can be carried out for example by heating with, for
example, chloracetaldehyde at 60 to 130 C, in particular 100 to 130 C, in
n-butanol as solvent and for a period of from 1 hour to 10 days, in particular
3 to 6
days.
The amination (stages A3, B4 and C2 respectively) can be carried out for
example by heating with the appropriate amine at 90-180 C, in particular 90 C,
for a period of from 1 hour to 24 hours, in particular 1 hour to 16 hours. The
heating can take place by means of conventional heating or else by means of
microwave radiation through a suitable apparatus. The use of an auxiliary base
such as, for example, K2CO3 or Et3N is not always necessary. The use of a
solvent such as, for example, acetonitrile, Et0H, n-BuOH or NMP is not always
necessary. It is possible to use for the amination for example the so-called
Buchwald-Hartwig cross-coupling reaction. The Buchwald-Hartwig cross-coupling
reaction can be carried out for example in accordance with one of the
references
D. Zim, S.L. Buchwald, Org. Lett., 5:2413-2415 (2003) or S. Urgaonkar, M.
Nagarajan, J.G. Verkade, J. Org. Chem., 68:452-459 (2003).
The reaction to give the 3-bromo intermediate (stages A2, B2 and C3) can take
place by introducing the precursor compound into chloroform and adding the N-
bromosuccinimide at ¨5 to 30 C, in particular at 0 to 10 C, followed by
reaction
for 1 hour to 2 days, in particular 5 to 15 hours, at 0 to 30 C, in particular
at 15 to
25 C. However, alternative synthesis routes for preparing the 3-halo
intermediates of the invention are also known to the skilled worker.
Stages A4, B3 and C4 can be carried out for example by introducing the
precursor compound into dimethoxyethane and adding a boronic acid in the
presence of a palladium(0) source, for example bis(dibenzylidene-

CA 02620534 2013-05-08
- 25 -
acetone)palladium(0), of a ligand, for example tri-o-tolylphosphine and of a
base, for example sodium bicarbonate, and by heating under reflux for 5 to 40
hours, in particular 10 to 20 hours.
Where the preparation of the starting compounds is not described, they are
known
or can be prepared in analogy to known compounds or methods described herein.
The isomer mixtures can be fractionated by conventional methods such as, for
example, crystallization, chromatography or salt formation into the isomers
such
as, for example, into the enantiomers, diastereomers or E/Z isomers, as long
as
the isomers are not in equilibrium with one another.
The salts are prepared in a conventional way by adding the equivalent amount
or
an excess of a base or acid, which is in solution where appropriate, to a
solution
of the compound of the formula I, and removing the precipitate or working up
the
solution in a conventional way.
Additional reference is made to the examples for merely exemplary details of
the
synthesis.
The invention further relates also to intermediates of the invention as
described
herein.
Compounds of the invention are suitable as kinase inhibitors, in particular of
tyrosine and serine/threonine kinases. The compounds of the invention of the
general formula I are inter alia inhibitors of the protein kinase C family,
such as, for
example, PKC theta, delta, iota, alpha and zeta.
An inhibitor of a kinase can therefore be employed on the one hand for
investigating the mechanisms of functioning of the kinase, in particular
research
into a disorder which derives from a dysfunction of the kinase. However, it is
also
possible for a disorder derived from the dysfunction of the kinase to be
treated or
prevented using the kinase inhibitor.

CA 02620534 2008-02-28
SRG/US/53343 - 26 -
ALJ/TDS
The invention therefore further relates to the use of a compound of the
invention
of the general formula I for producing a pharmaceutical composition, in
particular
for inhibiting a cellular kinase, preferably kinases of the protein kinase
(PK) family
and in this connection in particular for inhibiting kinases of the PKC
subfamily,
very especially for inhibiting the PKC theta kinase, and for the treatment or
for the
prophylaxis of a disorder which is associated with overexpression or mutation
of a
cellular kinase, in particular of such a cellular kinase.
It has additionally been found that, surprisingly, the compounds of the
invention
are also inhibitors of kinases of the ALK family. ALK means "activin receptor-
like
io kinase" or "activin-like kinase". In this connection, the compounds of
the invention
act on ALK1, ALK2, ALK4 and ALK5, in particular on ALK1 and ALK5. The
compounds of the invention are therefore also suitable for the treatment or
prophylaxis of disorders which are associated with overexpression or mutation
of
a kinase of the ALK family, in particular ALK1 and ALK5.
is In one embodiment of the invention, the disorder is a disorder from the
group
consisting of epidermal hyperproliferation such as psoriasis, Alzheimer's,
autoinflammatory disorders, fibroses, impaired wound healing, diabetic
retinopathy, nephropathy, age-related macular degeneration, Crohn's disease,
exaggerated immune response, contact dermatitis, atopic dermatitis, multiple
20 sclerosis, ALS, diabetes, asthma.
In another embodiment of the invention, the disorder is a disorder from the
group
consisting of benign tumors, malignant tumors, leukemia such as myeloblastic
leukemia, lymphoma, sarcoma such as osteosarcoma or chondrosarcoma,
neuroblastoma, Wilm's tumor, malignant neoplasms of the bladder, breast, lung,
25 pancreas, prostate, kidney, neoplasms of epithelial origin such as
carcinoma of
the breast or metastases thereof.
In a further embodiment of the invention, compounds of the invention are used
for
modulating, in particular reducing, an immune response, for example after a
transplantation has taken place to prevent rejection of an organ.

CA 02620534 2008-02-28
SRG/US/53343 - 27 -
ALJITDS
A pharmaceutical composition of the invention can be produced by mixing a
physiologically effective dose of a compound of the invention with at least
one
pharmaceutical excipient and manufacturing a desired dosage form.
A suitable physiologically effective dose is for example an amount of from 1
to
1000 mg, in particular from 50 to 500 mg, per dose unit per day for a person
weighing 75 kg, it being possible to give the dose as a single dose to be
administered once or divided into 2 or more daily doses.
The pharmaceutical manufacture of a pharmaceutical composition of the
invention
can take place in a manner customary in the art. Examples of suitable counter
ions
for ionic compounds are Na+, K+, Li+ or cyclohexylammonium, or Cl, Br,
acetate,
trifluoroacetate, propionate, lactate, oxalate, malonate, maleate, citrate,
benzoate,
salicylate etc. Examples of suitable solid or liquid pharmaceutical
presentations are
granules, powders, coated tablets, tablets, (micro)capsules, suppositories,
syrups,
solutions, ointments, suspensions, emulsions, drops or solutions for injection
(i.v.,
i.p., i.m., s.c.) or atomization (aerosols), transdermal systems, and products
with
protracted release of active ingredient which are produced by using
conventional
aids such as carriers, disintegrants, binders, coating agents, swelling
agents,
glidants or lubricants, and preservatives, stabilizers, wetting agents or
emulsifiers;
salts to alter the osmotic pressure or buffers, flavorings, sweeteners and
solubilizers. Carrier systems which can also be used are surface-active
excipients
such as salts of bile acids or animal or vegetable phospholipids, but also
mixtures
thereof, and liposomes or constituents thereof. Excipients which may be
mentioned
are magnesium carbonate, magnesium stearate, gum Arabic, titanium dioxide,
lactose, mannitol and other sugars, talc, milk protein, gelatin, starch,
cellulose and
its derivatives, animal and vegetable oils such as fish liver oil, sunflower,
peanut or
sesame oil, polyethylene glycols and solvents such as, for example, sterile
water
and monohydric or polyhydric alcohols, for example glycerol. Preferred dosage
forms are for topical application (ointments, transdermal systems, patches,
dressings), for oral administration (tablets, coated tablets, solutions,
powders) or
for parenteral use (suspension, injection).

CA 02620534 2013-05-08
- 28 -
A pharmaceutical composition of the invention can be produced by mixing at
least
one inhibitor used according to the invention in defined dose with a
pharmaceutically suitable and physiologically tolerated carrier and, where
appropriate, further suitable active ingredients, additives or excipients with
a
defined dose of inhibitor and manufacturing the desired dosage form. These
pharmaceutical products are likewise an aspect of the present invention.
Finally, the invention also relates to a method for the treatment or
prophylaxis of a
disorder which is associated with overexpression of a cellulose kinase, where
a
pharmaceutical composition comprising a physiologically effective dose of a
lo compound as described herein is administered to a person suffering from
or
under threat of suffering from the disorder.
The invention is explained in more detail below by means of examples which
represent merely exemplary embodiments.
Preparation of the starting materials:
6-Chloroimidazo[1,2-b]pyridazine (Example 1.0 OP 3055)
.7nr.NH2
CIN
5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7
ml
(40 mmol) of chloracetaldehyde (55% strength in water) in 15 ml of n-butanol
at
120 C for a period of 5 days. After the reaction was complete, the reaction
mixture
was added to saturated sodium bicarbonate solution and extracted three times
with
ethyl acetate. The combined organic phases were then washed with sat. sodium
chloride solution and dried over sodium sulfate, and the solvent was removed
in
vacuo. In the final purification by chromatography on silica gel, 4.17 g (70%)
of the
desired product were isolated in the form of an amorphous white solid.

CA 02620534 2008-02-28
SRG/US/53343 - 29 - ALSTDS
1H-NMR (CDCI3, stored over molecular sieves): 6 = 7.06 (d, 1H); 7.79 (d, 1H);
7.92,
(d, 1H); 7.96 (d, 1H) ppm.
3-Bromo-6-chloroimidazot1,2-13]pyridazine (Example 1.1 OP 3056)
cr
Br
478 mg (3.11 mmol) of 6-chloroimidazo[1,2-b]pyridazine were introduced into 10
ml
of chloroform under argon and, while cooling in ice, 664 mg (3.73 mmol) of N-
bromo-
succuinimide were added. After the addition was complete, the reaction mixture
was
stirred at room temperature overnight. The reaction mixture was then mixed
with
io water and ethyl acetate and, after addition of saturated sodium
bicarbonate solution,
the phases were separated. The aqueous phase was extracted three more times
with ethyl acetate. The combined organic phases were then washed with sat.
sodium chloride solution and dried over sodium sulfate. In the final removal
of the
solvent in vacuo, the desired product was isolated in quantitative yield in
the form of
is an amorphous white solid which was employed without further
chromatographic
purification in subsequent reactions.
1H-NMR (CDCI3, stored over molecular sieves): 6 = 7.12 (d, 1H); 7.79 (s, 1H);
7.90,
(d, 1H) ppm.
20 6-Chloro-3-iodoimidazo[1,2-b]pyridazine (Example 1.2)
CI CI N

CA 02620534 2008-02-28
SRG/US/53343 - 30 -
ALJ/TDS
14 g of 6-chloroimidazo[1,2-b]pyridazine (Example 1.0) were suspended in 364
ml
of acetonitrile, and 20.51 g of N-iodosuccinimide were added. The mixture was
stirred at RT for 19 hours. A further 4.31 g of N-iodosuccinimide were added,
and
the mixture was stirred for 24 hours. The reaction was cooled and the
precipitated
solid was filtered off with suction, washed with acetonitrile and dried. 17.67
g of the
desired product are obtained.
1H-NMR (300 MHz, d6-DMS0): 8 = 7.40 (d, 1H); 7.95 (s, 1H); 8.19 (d, 1H) ppm.
Preparation of the intermediates of the invention:
Imidazot1,2-14pyridazin-6-yl-(3-pyrrolidin-1-ylpropyl)amine (Example 1.3)
N
Cl,rJNA() ____________________________
CriN
100 mg (0.65 mmol) of 6-chloroimidazo[1,2-b]pyridazine were introduced into 9
ml of
tetrahydrofuran and 3 ml of dimethylformamide under argon. 83 mg (0.65 mmol,
1.0 eq.) of 1-(3-aminopropyl)pyrrolidine, 60 mg (0.065 mmol, 0.1 eq.) of
(dibenzylideneacetone)palladium(0), 41 mg (0.065 mmol, 0.1 eq.) of rac. 2,2`-
bis(diphenylphosphino)-1,1`binaphthyl and 125 mg (1.3 mmol, 2.0 eq) of sodium
tort-
butoxide were successively added, and the mixture was then heated at 80 C for
4 h.
The reaction mixture was then mixed with water and ethyl acetate and, after
addition
of saturated sodium bicarbonate solution, the phases were separated. The
aqueous
phase was extracted three more times with ethyl acetate. The combined organic
phases were then washed with sat. sodium chloride solution and dried over
sodium
sulfate. In the final purification by chromatography on silica gel, 53 mg
(39%) of the
desired product were isolated in the form of an amorphous white solid.

CA 02620534 2008-02-28
SRG/US/53343 - 31 -
ALJ/TDS
1H-NMR (CDCI3, stored over molecular sieves): 6 = 1.77-1.89 (m, 6H); 2.54 (m,
4H); 2.66 (m, 2H); 3.43 (m, 2H); 6.18 (s. br, 1H); 6.31 (d, 1H); 7.44(d, 1H);
7.57,
(d, 1H); 7.61 (d, 1H) ppm.
LC-MS (ACN/H20 0.01% HCOOH; 33x4.6x1.5p ODSII, Gradient: 100% H20
90% ACN in 4.5 min): t = 0.41 min; m/z = 246 [M+H] 38%; 123 [M+H]+ 100%;
6-Chloro-3-phenylimidazot1,2-Npyridazine (Example 1.4)
Br
500 mg (2.15 mmol) of 3-bromo-6-chloroimidazo[1,2-b]pyridazine were introduced
into 25 ml of dimethoxyethane under argon. 290 mg (2.4 mmol, 1.1 eq.) of
phenyl
io boronic acid, 250 mg (0.43 mmol, 0.2 eq.) of
bis(dibenzylideneacetone)palladium(0)
and 130 mg (0.43 mmol, 0.2 eq.) of tri-o-tolylphosphine, 2.2 ml of saturated
sodium
bicarbonate solution, were successively added, and the reaction mixture was
heated
under reflux for 15 hours.
The reaction mixture was then mixed with ethyl acetate and, after addition of
saturated sodium bicarbonate solution, the phases were separated. The aqueous
phase was extracted three more times with ethyl acetate. The combined organic
phases were then washed with sat. sodium chloride solution and dried over
sodium
sulfate. In the final purification by chromatography on silica gel, 239 mg
(48%) of the
desired product were isolated.
1H-NMR (CDCI3, stored over molecular sieves): 6 = 7.02 (d, 1H); 7.35 (m, 1H);
7.43
(m, 2H); 7.89 (d, 1H); 7.95 ¨ 8.0 (m, 3H) ppm.
MS (ES+): m/z = 230 (100%)([M+H]; 232 (45%).

CA 02620534 2008-02-28
SRG/US/53343 - 32 -
ALJ/TDS
2-(3-Bromoimidazo[1,2-b]pyridazin-6-ylamino)ethanol (Example 1.5)
________________________________________________________________ HONAN,14-.?
Br Br
400 mg (1.72 mmol) of 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2.0 ml
(33.4 mmol) of ethanolamine were stirred at 90 C for 16 h. After cooling, the
mixture
was concentrated. The resulting residue was purified by chromatography
(DCM/Et0H 9:1). 282 mg of the product were obtained.
1H-NMR (300 MHz; d6-DMS0): = 3.28 ¨ 3.34 (m, 2H, covered by solvent); 3.56 ¨
3.61 (m, 2H); 4.74 (t, 1H); 6.71 (d, 1H); 7.13 (t, 1H); 7.43 (s, 1H); 7.64 (d,
1H) ppm.
MS (El+): m/z = 256; 258 (M+H)+. [mol. weight = 257.09].
2-(3-lodoimidazo(1,2-14pyridazin-6-ylamino)ethanol (Example 1.6)
Hos,N
N
562 mg (2.0 mmol) of 6-chloro-3-iodoimidazo[1,2-b]pyridazine and 2.35 ml
(39.2 mmol) of ethanolamine were stirred at 90 C for 16 h. After cooling, the
mixture
was concentrated. The resulting residue was purified by chromatography
(DCM/Et0H 9:1). 224 mg of the product were obtained.
1H-NMR (300 MHz; d6-DMS0): 8 = 3.27 ¨ 3.35 (m, 2H, covered by solvent); 3.58 ¨
3.63 (m, 2H); 4.72 (t, 1H); 6.67 (d, 1H); 7.06 (t, 1H); 7.42 (s, 1H); 7.59 (d,
1H) ppm.
MS (ESI+): m/z = 305 (M+H)+. [mol. weight = 304.09].

CA 02620534 2008-02-28
SRG/US/53343 - 33 - ALJ/TDS
The following are prepared in an analogous manner:
Table 1:
Mol. weight
Example/
Structure and name of the main isomer 1H-NMR
No. MS (ES+)
358 1.7 r'rN (CDCI3, stored over MW:
846 molecular sieves): 264.12
/
CI - 6 = 7.12 (d, 1H); 7.38 (m,
NN
1H); 7.46 (m, 1H); 7.94 (m, MS (ES+)
42H); 8.07 (m, 1H); 8.09 (s, [M+1] +:
CI 1H) ppm. 264
6-Chloro-3-(3-chloro-phenyI)-
imidazo[1,2-13]pyridazine .
358 1.8 r\rN (CDCI3, stored over MW:
860 molecular sieves): 233.66
CIN-N---1...1 6 = 4.04 (s, 3H); 7.04 (d, 1H);
7.92 (d, 2H); 7.96 (s, 1H); MS (ES+)
/ I 8.03 (s, 1H); 8.25 (s, 1H) [M+1] +:
N-N ppm. 234
/
6-Chloro-3-(1-methy1-1H-pyrazol-
4-yI)-imidazo[1,2-b]pyridazine
358 1.9 N (CDCI3, stored over MW:
rf.---...
861 molecular sieves): 235.70
/
CIN-N 6 = 7.14 (d, 1H); 7.48 (m,
\ S
---1 1H); 7.64 (m, 1H); 8.02 (d, MS
(ES+)
1H); 8.07 (s, 1H); 8.34 (m, [M+1] +:
1H) ppm. 236
=
6-Chloro-3-thiophen-3-yl-imidazo
[1,2-b]pyridazine
601 1.10 . e\r:-,N MW:
352 244.69
6
CI
MS (CI+)
11
NH2 245 10
3-(6-Chloro-imidazo[1,2-b]pyridazin
-3-yI)-phenylamine

CA 02620534 2008-02-28
SRG/US/53343 - 34 - ALJ/TDS
601 1.11
MW:
373 286.72
1 /
Cl NMS (CI+)
287
/0
N-(3-(6-Chloro-imidazo[1,2-13]pyrida
zin-3-y1)-phenyl]acetamide
602 1.12
e"Nr..1.1.N MW:
147 274.67
2
Cl N
MS (CI+)
275
N43
_
0
6-Chloro-3-(3-nitro-phenyl)-imidazo
[1,2-b]pyridazine
602 1.13 MW:
564 278.14
2 2N _11%1 /
CI N
MS (CI+)
279
* CI
6-Chloro-3-(3-chloro-4-methyl-pheny
I)-imidazo[1,2-b]pyridazine
603 1.14 (400 MHz, d6-DMS0): MW:
262 8 = 3.87 (s, 3H); 7.49 (d, 1H);
260.68
1 7.62 (m, 1H); 7.66¨ 7.67 (m,
ci N 1H); 8.24 ¨ 8.26 (m, 1H); MS
(ES+)
---- = 8.32 (d, 1H); 8.55 (s, 1H)
261; 263 (Cl
/ 0 ppm. Isotopes)
N
6-Chloro-3-(2-methoxy-pyridin-4-yI)-
imidazo[1,2-b]pyridazine
603 1.15 (300 MHz, d6-DMS0): MW:
frN
013 8 = 3.89 (s, 3H); 6.96 ¨ TOO
260.68
CI .N=N (m, 1H); 7.38 (d, 1H); 8.24 ¨
8.28 (m, 2H); 8.28 ¨ 8.32 (m, MS (ES+)
1H); 8.82 ¨ 8.83 (m, 1H) 261; 263
(CI
,,r ppm. Isotopes)
0
6-Chloro-3-(6-methoxy-pyridin-3-yI)-
imidazo[1,2-b]pyridazine

CA 02620534 2008-02-28
SRG/US/53343 - 35 - ALJ/TDS
602 1.16 (300 MHz, d6-DMS0): MW:
976 6 = 3.84 (s, 6H); 6.58 (t, 1H);
289.72
8 7.32 (d, 2H); 7.43 (d, 1H);
01' 8.30 (d, 1H); 8.40 (s, 1H) MS
(ES+)
ppm. 290; 292
(CI
Isotopes)
0\
6-Chloro-3-(3,5-dimethoxy-phenyI)-imidazo[1,2-
b]pyridazine
601 1.17 (300 MHz, d6-DMS0):
957 8 = 3.69 (s, 3H); 3.83 (s, 6H);
6 7.38 (d, 1H); 7.40 (s, 2H);
CI -N 8.25 (d, 1H); 8.33 (s, 1H)
ppm.
0\
6-Chloro-3-(3,4,5-trimethoxy-phenyI)-
imidazo[1,2-b]pyridazine
601 1.18 (400 MHz, d6-DMS0):
957 8 = 7.45 (d, 1H); 7.73 - 7.78
2
CI (m, 2H); 8.31 (d, 1H); 8.36 -
8.39 (m, 1H); 8.46 (m, 2H)
F PPm=
F F
6-Chloro-3-(3-trifluoromethyl-phenyI)-
imidazo[1,2-blpyridazine
601 1.19 (300 MHz, d6-DMS0):
957 6 = 7.36 - 7.40 (m, 2H); 7.46
0 A )1 / (d, 1H); 7.90- 7.93 (m, 1H);
N
8.02 - 8.05 (m, 1H); 8.18 (s,
S 1H); 8.32 (d, 1H); 8.43 (s,
1H) ppm.
' *
3-Benzo[b]thiophen-2-y1-6-chloro-imidazo[1,2-
Npyridazine
e
601 1.20 (300 MHz, d6-DMS0): MW: \r--N
370 6 = 3.80 (s, 3H); 6.94 - 6.98
259.70
(m, 1H); 7.37 - 7.45 (m, 2H);
CI N 7.63 - 7.66 (m, 2H); 8.26 (d, MS
(ES+)
1H); 8.32 (s, 1H) ppm. 260; 262
(CI
Isotopes)
0\
6-Chloro-3-(3-methoxy-phenyI)-imidazo[1,2-
b]pyridazine

CA 02620534 2008-02-28
SRG/US/53343 - 36 - ALJ/TDS
601 1.21 (400 MHz, d6-DMS0):
979 8 = 7.36 - 7.38 (m, 1H); 7.43
6CIN ,.N (d, 1H); 7.62 - 7.66 (m, 1H);
8.09 - 8.11 (m, 1H); 8.13 (m,
1H); 8.29 (d, 1H); 8.41 (s,
io 0 F 1H) ppm.
6-Chloro-3-(3-trifluoromethoxy-phenyI)-
imidazo[1,2-b]pyridazine
602 1.22 (300 MHz, d6-DMS0): MW:
059 5 = 7.45 (d, 1H); 7.77 (d, 1H);
298.56
8.09 (dd, 1H); 8.29 (d, 1H);
-1µ1 8.36 (d, 1H); 8.43 (s, 1H) MS
(ES+)
ppm. 298; 300;
302 (Cl
II CI Isotopes)
CI
6-Chloro-3-(3,4-dichloro-phenyI)-imidazo[1,2-
b]pyridazine
602 1.23 (300 MHz, d6-DMS0):
059 8 = 7.42 (d, 1H); 7.55 - 7.61
7 (M, 1H); 8.08 - 8.13 (m, 1H);
Cr 1\1 8.27 - 8.31 (m, 2H); 8.36 (s,
1H) ppm.
lip CI
6-Chloro-3-(3-chloro-4-fluoro-phenyI)-
imidazo[1,2-b]pyridazine
602 1.24 (300 MHz, d6-DMS0):
059 8 = 7.45 (d, 1H); 7.70 - 7.75
6 (m, 1H); 7.82 - 7.85 (m, 1H);
CI N 8.31 (d, 1H); 8.41 - 8.45 (m,
2H); 8.51 (m, 1H) ppm.
110
3-(6-Chloro-imidazo[1,2-b]pyridazin-3-yI)-
benzonitrile
603 1.25 (400 MHz, d6-DMS0): MW:
336 = 7.05 - 7.10 (m, 1H); 7.36
263.66
3
CI (d, 1H); 7.72 - 7.74 (m, 1H);
7.87 - 7.91 (m, 1H); 8.22 - MS (ES+)
8.25 (m, 2H); 10.24 (br s, 1H) 264; 266 (Cl
F ppm. Isotopes)
OH
4-(6-Chloro-imidazo[1,2-b]pyridazin-3-yI)-2-
fluoro-phenol

CA 02620534 2008-02-28
SRG/US/53343 - 37 -
ALJ/TDS
1.26 N MW:
307.76
)
CI N
MS (ES+)
Ia 308; 310 (CI
s=o Isotopes)
6-Chloro-3-(3-methanesulfonyl-phenyl)-
imidazo[1,2-1Apyridazine
600 1.27 e\ r-ts1/ MW:
073 324.23
0
4 , \ MS
(El+)
Br
323/325
(3-Bromo-imidazo[1,2-b]pyridazin-6-
yl)-(3-pyrrolidin-1-yl-propy1)-amine
6-Chloro-3-naphthalen-2-ylimidazo[1,2-b]pyridazine (Example 1.28)
CI
1111*
1.03 g of 6-chloro-3-naphthalen-2-ylimidazo[1,2-b]pyridazine were prepared
from
3.5 g (12.52 mmol) of 6-chloro-3-iodoimidazo[1,2-b]pyridazine (Example 1.2)
and
2.37 g (13.78 mmol) of 2-naphthylboronic acid (CAS No. 32316-92-0) in analogy
to
Example 1.4.
1H-NMR (400 MHz, d6-DMS0): 8 = 7.43 (d, 1H); 7.51 ¨ 7.57 (m, 2H); 7.92 ¨ 7.98
(m, 2H); 8.02 ¨ 8.05 (m, 1H); 8.13 ¨ 8.16 (m, 1H); 8.31 (d, 1H); 8.43 (s, 1H);
8.69
(s, 1H) ppm.

CA 02620534 2008-02-28
SRG/US/53343 - 38 -
ALJ/TDS
Preparation of the final products of the invention:
Method A: (3-phenylimidazor 1,2-14pyridazin-6-y1)-(3-pyrrolidin-1-ylpropy1)-
amine (Example 2.0)
"N N-
CI N
100 mg (0.435 mmol) of 6-chloro-3-phenylimidazo[1,2-b]pyridazine were
dissolved in
a mixture of 6 ml of tetrahydrofuran and 2 ml of dimethylformamide under
argon.
56 mg (0.435 mmol, 1.0 eq.) of 1-(3-aminopropyl)pyrrolidine, 40 mg (0.07 mmol,
0.16 eq.) of bis(dibenzylideneacetone)palladium(0) (Pd2dba3), 27 mg (0.0435
mmol,
0.1 eq.) of rac. 2,2`-bis(diphenylphosphino)-1,1`-binaphthyl (rac-BINAP) and
84 mg
io (0.87 mmol, 2 eq.) of sodium tert-butoxide (NaOtBu) were successively
added, and
the reaction mixture was heated at 80 C for 4 hours.
The reaction mixture was then mixed with ethyl acetate and, after addition of
water,
the phases were separated. The aqueous phase was extracted three more times
with ethyl acetate. The combined organic phases were then washed with sat.
is sodium chloride solution and dried over sodium sulfate. After multiple
purification on
silica gel in the final chromatographic fractionation, 9 mg (6%) of the
desired product
were isolated in pure form.
1H-NMR (CDCI3, stored over molecular sieves): 6 = 1.8 (m, 4H); 1.88 (m, 2H);
2,55
(m, 4H); 2.68 (t, 2H); 3.51 (m, 2H); 6.19 (s, br. 1H); 6.38 (d, 1H); 7.33 (m,
1H); 7.46
20 (m, 2H); 7.63 (d, 1H); 7.79 (s, 1H); 8.12 (d, 2H) ppm.
MS (ES+): m/z = 322 (100%)([M+Hr.

CA 02620534 2008-02-28
SRG/US/53343 - 39 -
ALJ/TDS
The following are prepared in an analogous manner:
Table 2:
Mol. weight
Example
Structure and name of the main isomer 1H-NMR MS (ES+)
No. [M+1]
2.1 (CDCI3, stored over
molecular sieves): 6 = 1.86
(m, 2H); 2.50 (m, 4H); 2.54
0)
(m, 2H); 3.50 (m, 2H); 3.75
(m, 4H); 6.02 (s, br. 1H); 6.41
(d, 1H); 7.46 (m, 2H); 7.67
(3-Morpholin-4-yl-propyI)-(3-phenyl- (d, 1H); 7.80 (s, 1H); 8.12 (d,
imidazo[1,2-b]pyridazin-6-yI)-amine
2H) ppm.
2.2 (CDCI3, stored over MW:
molecular sieves): 6 = 1.81
CNNN-N 355.87
(m, 4H); 1.89 (m, 2H); 2.56
(m, 4H); 2.68 (m, 2H); 3.53 MS (ES+)
CI (m, 2H); 6.34 (s, br. 1H); 6.39
+:
[3-(3-Chloro-phenyl)-imidazo[1,2-b] (d, 1H); 7.29(m, 1H); 7.38 [M+1]
pyridazin-6-yI]-(3-pyrrolidin-1-yl- (dd, 1H); 7.64 (d, 1H); 7.81
356
propyI)-amine (s, 1H); 7.95 (m, 1 H); 8.30
(s, 1H) ppm.
2.3 \r.N (CDCI3, stored over MW:
molecular sieves): 6 =1.88
rNNN-N 371.87
(m, 2H); 2.50 (m, 4H); 2.57
oJ
(m, 2H); 3.53 (m, 2H); 3.75 MS (ES+)
ci (m, 4H); 6.08 (m, 1H); 6.45
(d, 1H); 7.29(m, 1H); 7.38 [M+1]+:
[3-(3-Chloro-phenyI)-imidazo[1,2-b]
pyridazin-6-y11-(3-morpholin-4-yl- (dd, 1H); 7.67 (d, 1H); 7.82
372
propyI)-amine (s, 1H); 7.94 (dd, 1H); 8.32
(d, 2H) ppm.
2.4 MW:
-/N 385.90
MS (Cl+)
CI
386
[3-(3-Chloro-pheny1)-imidazo[1,2-13]
pyridazin-6-yI]-methyl-(3-morpholin
-4-yl-propyI)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 40 -
ALJ/TDS
2.5(CDCI3, stored over
4,1,õ molecular sieves): = 1.45
y HN N (s, 9H); 2.04 (m, 1H); 2.34
0
(m, 1H); 3.45-3.60 (m, 3H);
ci 3.77 (m, 1H); 4.46 (m, 1H);
4.65(m, 1H); 6.48 (d, 1H);
3-[3-(3-Chloro-phenyI)-imidazo[1,2- 7.28 (m, 1H); 7.37 (m, 1H);
blpyridazin-6-ylamino]-pyrrolidine- 7.70 (m, 1H); 7.84 (m, 2H);
1-carboxylic acid tert-butyl ester 8.32 (m, 1H) ppm.
2.6N MW:
394.48
NN
NN
MS (ES+)
IP [Iv 395
N-{346-(3-Morpholin-4-yl-propylami
no)-imidazo[1,2-b]pyridazin-3-y1Fp
henyI}-acetamide
2.7
MW:
385.94
MS (ES+)
386
CI
(S)-N*4*-[3-(3-Chloro-phenyh-imida
zo[1,2-b]pyridazin-6-yI]-N*1*,N*1*-
diethyl-pentane-1,4-diamine
2.8 MW:
385.94
N N
MS (ES+)
386
411 CI
(R)-N*4*-13-(3-Chloro-pheny1)-imida
zo[1,2-b]pyridazin-6-y1]N*1*,N*1*-
diethyl-pentane-1,4-diamine
2.9 MW:
413.91
N
ms(c,+)
.1,0TNJ 414
* CI
0
4-[3-(3-Chloro-pheny1)-imidazo[1,2-
b]pyridazin-6-y11-piperazine-1-carb
oxylic acid tert-butyl ester

CA 02620534 2008-02-28
SRG/US/53343 - 41 -
All/TDS
2.10 MW:
0õ0
379.87
-1"s1
N N N
MS (C1+)
380
CI
243-(3-Chloro-pheny1)-imidazo[1,2-
lApyridazin-6-ylaminoFethanesulfon
ic acid dimethylamide
2.11 rrN(CDCI3, stored over
molecular sieves): 6 = 1.09 (t,
6H); 1.85 (m, 2H); 2.43 (s,
3H); 2.53-2.69 (m, 6H); 3.49
CI (m, 2H); 6.40 (d, 1H); 6.76
(m, 1H); 7.39 (d, 1H); 7.62
(d, 2H); 7.75 (s, 1H); 7.93 (m,
N'-[3-(3-Chloro-4-methyl-phenyl)-im
1H); 8.01 (m, 1H) ppm.
idazo[1,2-b]pyridazin-6-yli-N,N-die
thyl-propane-1,3-diamine
/ (300 MHz, d6-DMS0): =
2.12
3.03 -3.08 (m, 2H); 3.63 -
H 3.70 (m, 5H); 3.73 (s, 6H);
11 1/ 6.65 (d, 1H); 7.15- 7.26 (m,
3H); 7.54 (s, 2H); 7.64 - 7.71
ck (m, 2H); 7.92 (s, 1H); 8.46 -
8.48 (m, 1H) ppm.
(2-Pyridin-2-yl-ethyl)13-(3,4,5-trinnethoxy-
phenyl)-imidazo[1,2-b]pyridazin-6-y11-
amine
2.13 (400 MHz, d6-DMS0): 6 =
N2.58 (s, 3H); 4.58 - 4.60 (m,
2H); 6.86 (d, 1H); 7.39 - 7.40
II H
0 OM 2H); 7.47 - 7.50 (m, 1H);
7.79- 7.86 (m, 3H); 7.99 (s,
1H); 8.09 - 8.12 (m, 1H);
1-(3-{6-[(Pyridin-4-ylmethyp-amino]- 8.49 - 8.50 (m, 2H); 8.67 -
imidazo[1,2-b]pyridazin-3-yll-phenyl)- 8.68 (m, 1H) ppm.
ethanone
2.14 (400 MHz, d6-DMS0): 6 =
0.93 (t, 3H); 1.58 - 1.67 (m,
2H); (m, 2H, covered by
solvent); 2.61 (s, 3H); 6.70
(d, 1H); 7.09 - 7.11 (m, 1H);
1-[3-(6-Propylamino-imidazo[1,2- 7.55 - 7.59 (m, 1H); 7.73 (d,
blpyridazin-3-y1)-phenyl]ethanone
1H); 7.83 - 7.86 (m, 1H);
7.97 (s, 1H); 8.28 -8.31 (m,
1H)_; 8.96 - 8.97 (m, 1H)

CA 02620534 2008-02-28
SRG/US/53343 - 42 -
ALJ/TDS
PPm=
2.15 o . (300 MHz, d6-DMS0): = MW:
1.40- 1.52 (m, 2H); 1.98- 354.41
2.03 (m, 2H); 3.34 - 3.42 (m, MS (ES+)
411 0 2H); 3.78 - 3.90 (m, 9H); 355
6.43 (t, 1H); 6.65 (d, 1H);
-0
[3-(3,5-Dimethoxy-phenyI)-imidazo[1,2- 7.02 - 7.05 (m, 1H); 7.36 (d,
b]pyridazin-6-y1]-(tetrahydro-pyran-4-y1)- 2H); 7.71 (d, 1H); 7.90 (s,
amine
1H) ppm.
2.16 o (300 MHz, d6-DMS0): 8 = MW:
1.38 - 1.52 (m, 2H); 1.98- 310.36
N
2.03 (m, 2H); 3.38 - 3.46 (m, MS (ES+)
2H); 3.73 - 3.91 (m, 3H); 311
6.60 (d, 1H); 6.79- 6.82 (m,
OH
4[6-(Tetrahydro-pyran-4-ylannino)-
2H); 6.95 - 6.97 (m, 1H);
imidazo[1,2-b]pyridazin-3-y1]-phenol 7.66 - 7.69 (m, 2H); 7.91 -
7.94 (m, 2H); 9.54 (s, 1H)
ppm.
2.17 o (400 MHz, d6-DMS0): 8 =
1.42 - 1.52 (m, 2H); 1.96 -
N
2.01 (m, 2H); 3.34- 3.40 (m,
F
2H); 3.78 - 3.90 (m, 3H);
F F 6.70(d, 1H); 7.13 - 7.15 (m,
(Tetrahydro-pyran-4-yI)-[3-(3- 1H); 7.60 - 7.67 (m, 2H);
trifluoromethyl-phenyl)-imidazo[1,2- 7.77 (d, 1H); 8.02 (s, 1H);
b]pyridazin-6-y1Famine
8.24 - 8.27 (m, 1H); 8.77 (br
s, 1H) ppm.
2.18 o (300 MHz, d6-DMS0): ö =
1.44 - 1.57 (m, 2H); 2.10 -
N
2.16 (m, 2H); 3.53- 3.61 (m,
2H); 3.92 - 4.05 (m, 3H);
6.71 (d, 1H); 7.23- 7.25 (m,
1H); 7.28 - 7.39 (m, 2H);
7.76 - 7.81 (m, 2H); 7.94 -
(3-Benzo[b]thiophen-2-yl-imidazo[1,2-
7.97 (m, 1H); 8.00 (s, 1H);
b]pyridazin-6-y1)-(tetrahydro-pyran-4-y1)-
8.05 (br s, 1H) ppm.
amine
2.19 o (400 MHz, d6-DMS0): 8 = MW:
1.40 - 1.50 (m, 2H); 1.96- 325.37
2.00 (m, 2H); 3.39 - 3.45 (m, MS (ES+)
/
2H); 3.73- 3.83 (m, 1H); 326
3.85 - 3.89 (m, 5H); 6.66 (d,
0
1H); 6.90 (d, 1H); 7.06 - 7.07
[3-(6-Methoxy-pyridin-3-y1)-imidazo[1,2- (m, 1H); 7.73 (d, 1H); 7.81 (s,
b]pyridazin-6-y1]-(tetrahydro-pyran-4-y1)- 1H); 8.37 - 8.39 (dd, 1H)
amine

CA 02620534 2008-02-28
SRG/US/53343 - 43 -
ALJ/TDS
8.86(m, 1H) ppm.
2.20 (300 MHz, d6-DMS0): 8 = MW:
1.41 - 1.53 (m, 2H); 2.02 - 325.37
2.06 (m, 2H); 3.41 - 3.49 (m, MS (ES+)
/
2H); 3.75 - 3.93 (m, 6H); 326
6.73(d, 1H); 7.20 - 7.22 (m,
[3-(2-Methoxy-pyridin-4-yI)-imidazo[1,2- 1H); 7.61 -7.63 (m, 1H);
b]pyridazin-6-y1]-(tetrahydro-pyran-4-y1)-
7.77 (d, 1H); 7.82 (s, 1H);
amine
8.12 - 8.15 (m, 2H) ppm.
2.21 (400 MHz, d6-DMS0): =
1.39 - 1.48 (m, 2H); 1.97 -
H 1.99 (m, 2H); 3.23 (s, 3H);
to 3.48 - 3.53 (m, 2H); 3.82 -
s\--
3.84 (m, 2H); 3.96 -4.01 (m,
[3-(3-Methanesulfonyl-pheny1)-imidazo[1,2- 1H); 6.70 (d, 1H); 7.10 - 7.11
b]pyridazin-6-y1]-(tetrahydro-pyran-4-y1)-
. (m, 1H); 7.67 - 7.71 (m, 1H);
amine
7.76(d, 1H); 7.81 - 7.83 (m,
1H); 8.02 (s, 1H); 8.29 - 8.31
(m, 1H); 9.00 (m, 1H) ppm.
Method B: [3-(1-methyl-1H-pyrazol-4-yl)imidazotl,2-b]pyridazin-6-ylipyridin-3-
ylmethylamine (Example 3.0)
cIcN
(rH
ejl /
N-N
N-N
35 mg (0.15 mmol) of 6-chloro-3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-
13]pyridazine
were introduced into a mixture of 0.67 ml of tetrahydrofuran and 0.33 ml of
dimethylformamide under argon. Then 0.5 ml of a 0.45 M solution of pyridin-3-
ylmethylamine (0.225 mmol) in toluene was added. Addition of solutions of 1.72
mg
of Pd2dba3 (18.8 pmol) and 3.5 mg of rac-BINAP (56.3 pmol) in 0.91 ml of THF
and
31.7 mg of NaOtBu (0.3 mmol) in 0.91 ml of THF was followed by shaking of the
reaction mixture at 80 C for 12 h.

CA 02620534 2008-02-28
SRG/US/53343 - 44 -
ALJ/TDS
The reaction mixture was then mixed with 1 ml of water and 3 ml of ethyl
acetate.
The organic phase was separated off and freed of solvent. The crude product
obtained in this way was purified by HPLC. 8.7 mg (19%) of the desired product
were isolated.
HPLC-MS (analytical) of the purified product
Detection: UV = 254 nm; column: Purospher STAR RP18e, 125x4mm, 5 pm (Merck
KGaA, Darmstadt); eluent: A: H20/0.1% TFA, B: CH3CN/0.1% TEA, gradient: 5 to
95% B in 10 min; flow rate: 1 ml/min:
Retention time of the product = 3.85 min; MS of the product: m/z = 301 ([M+H])

CA 02620534 2008-02-28
SRG/US/53343 - 45 -
ALJ7TDS
=
The following are prepared in analogous manner:
Table 3:
HPLC-MSMol. weight/
Retention time
Example method MS
(HPLC-
Prot. No. Structure and Name of the main isomer (HPLC, UV 254
No. (see
MS)
nm) [min]
below)
[M+11-
KE1322- 3.1 A 4.59
301/
001-a
302
1%11 N
(3-Phenyl-imidazo[1,2-b]pyridazin-6
-yI)-pyridin-3-ylmethyl-amine
KE1322- 3.2 A 4.85
319/
002-a 320
N.j.
(3-Imidazol-1-yl-propy1)-(3-phenyl-
imidazo[1,2-b]pyridazin-6-y1)-amine
KE1322- 3.3 A .7.37
318/
003-a
319
FH
I*
(4-Fluoro-benzyI)-(3-phenyl-imidazo
[1,2-b]pyridazin-6-yI)-amine
KE1322- 3.4 A 8.36
306/
004-a 307
(r
Cyclohexylmethyl-(3-phenyl-imidazo
[1,2-b]pyridazin-6-yI)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 46 -
ALJ/TDS
KE1322- 3.5 JZX A 7.49
336/
005-a
337
/
H"
(2,4-Difluoro-benzyI)-(3-phenyl-
imidazo[1,2-b]pyridazin-6-yI)-amine
KE1322- 3.6 A 5.42
332/
006-a
333
iriT'' NN
.N
[3-(5-Methyl-1 H-pyrazol-4-y1)-propyl]-
(3-phenyl-imidazo[1,2-b]pyridazin-6-y1)
-amine
KE1322- 3.7 H 0 A 4.84 322/
007-a /N--f
323
14/
N
142-(3-Phenyl-imidazo[1,2-13]
pyridazin-6-ylamino)-ethylF
imidazolidin-2-one
KE1322- 3.8 A 4.71
323/
009-a 0 1
324
LN
,1=114/
N N
(2-Morpholin-4-yl-ethyl)-(3-phenyl-
imidazo[1,2-b]pyridazin-6-yI)-amine
KE1322- 3.9 N A 5.51
351/
010-a
352
Ns1
Al
N*1*,N*1*-Diethyl-N*4*-(3-phenyl-
imidazo[1,2-b]pyridazin-6-y1)-pentane
-1,4-diamine

CA 02620534 2008-02-28
SRG/US/53343 - 47 -
ALJ/TDS
KE1322- 3.10
A 5
323/
011-a 324
N,N-Diethyl-N'-(3-phenyl-imidazo
[1,2-b]pyridazin-6-yI)-propane-1,3-
diamine
KE1322- 3.11 A 4.84
307/
012-a 308
NUN
1%11 N
(3-Phenyl-imidazo[1,2-13jpyridazin-
6-y1)-(2-pyrrolidin-1-yl-ethyl)-amine
KE1322- 3.12 A 5.09
336/
013-a Ii
337
/
1%11 N
CI
[3-(3-Chloro-pheny1)-imidazo[1,2-13]
pyridazin-6-y1Fpyridin-3-ylmethyl-
amine
KE1322- 3.13 A 5.36
353/
014-a
354
NN /
Nj
IP CI
[3-(3-Chloro-phenyI)-imidazo[1,2-b]
pyridazin-6-y1]-(3-imidazol-1-yl-
propyI)-amine
KE1322- 3.14 A 7.73
353/
015-a
354
/
N N
*
* CI
[3-(3-Chloro-pheny1)-imidazo[1,2-13]
pyridazin-6-y1]-(4-fluoro-benzy1)-
amine

CA 02620534 2008-02-28
SRG/US/53343 - 48 -
ALJ/TDS
KE1322- 3.15
016-a fr-N A 8.87
341/
342
N N.NN
H
* CI
[3-(3-Chloro-pheny1)-imidazo[1,2-13]
pyridazin-6-yl]-cyclohexylmethyl-
amine
KE1322- 3.16 A 7.93
371/
017-a
372
N N
I. 4
# CI
[3-(3-Chloro-phenyl)-imidazo[1 ,2-h]
pyridazin-6-y1]-(2,4-difluoro-benzy1)-
amine
KE1322- 3.17 H 0 A 5.25 357/
019-a /NI
358
N
CI
1-{243-(3-Chloro-pheny1)-imidazo
[1,2-14pyridazin-6-ylaminol-ethyl}-
imidazolidin-2-one
KE1322- 3.18 A 5.87
386/
022-a N.v(
-114
387
N N
* CI
N*4*-[3-(3-Chloro-phenyI)-imidazo
[1,2-blpyridazin-6-A-N*1*,N*1*-
diethyl-pentane-1,4-diamine
KE1322- 3.19 A 5.53
358/
023-a 359
1N.,
* CI
N'-13-(3-Chloro-phenyl)-imidazo
[1,2-b]pyridazin-6-yli-N,N-diethyl-
propane-1,3-diamine

CA 02620534 2008-02-28
SRG/US/53343 - 49 -
ALJ/TDS
KE1322- 3.20 A 5.29
342/
024-a
CIN
343
N
N N
* CI
[3-(3-Chloro-phenyl)-imidazo
[1,2-b]pyridazin-6-y1]-(2-pyrrolidin-
1-yl-ethyl)-amine
KE1322- 3.21 N A 4.21
322/
026-a
323
/ 1
N-N
(3-Imidazol-1-yl-propy1)43-(1-
methyl-1H-pyrazol-4-y1)-imidazo
[1,2-13]pyridazin-6-y1Famine
KE1322- 3.22 A 6.19
322/
027-a
323
N
/
N-N
(4-Fluoro-benzy1)-13-(1-methyl-1H-
pyrazol-4-y1)-imidazo[1,2-13]-
pyridazin-6-y1Famine
KE1322- 3.23 N A 6.97
310/
028-a
311
N-N
Cyclohexylmethy1-13-(1-methy1-1H-
pyrazol-4-y1)-imidazo[1,2-b]pyridazin-
6-y1Famine

CA 02620534 2008-02-28
SRG/US/53343 -50- A
LJ/TDS
KE1322- 3.24 N A 6.17
340/
029-a
341
H"
/ 1
N-N
(2,4-Difluoro-benzy1)-[3-(1-methy1-
1H-pyrazol-4-y1)-imidazo[1,2-13]-
pyridazin-6-y1Famine
KE1322- 3.25 A 4.64
336/
030-a337
,114ki
14-N /
[3-(1-Methy1-1H-pyrazol-4-y1)-imidazo-
[I,2-13]pyridazin-6-y1H3-(5-methyl-
1H-pyrazol-4-y1)-propylFamine
KE1322- 3.26 H 0 A 4.09 326/
031-a //4--r
327
/ 1
N-N
14243-(I -Methyl-I H-pyrazol-4-y1)-
imidazo[I ,2-b]pyridazin-6-ylam ino]-
ethyll-im idazolidin-2-one
KE1322- 3.27 A 3.91
327/
033-a 0 1
328
=
=
/ I
N-N
[3-(1-Methy1-1H-pyrazol-4-y1)-
imidazo[1,2-b]pyridazin-6-y1]-
(2-morpholin-4-yl-ethyl)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 51 -
ALJ/TDS
KE1322- 3.28A 4.6
355/
034-a
356
===)N,,..,/-,J,ilf- 3
Is NN(
/ I
N-N
N*1*,N*1*-Diethyl-N*4*-[3-(1-methyl
-1H-pyrazol-4-y1)-imidazo[1,2-13]-
pyridazin-6-01-pentane-1,4-diamine
KE1322- 3.29 A 4.29
327/
035-a
328
/ I
14-1µ1
N,N-Diethyl-N'-[3-(1-methy1-1H-
pyrazol-4-y1)-imidazo[1,2-b]pyridazin-
6-yli-propane-1,3-diamine
KE1322- 3.30 A 4.11
311/
036-a 312
/
N-N
[3-(1-Methy1-1H-pyrazol-4-y1)-
imidazo[1,2-b]pyridazin-6-y1F
(2-nvrrolidin-1-1/1-ethyll-amine
KE1322- 3.31 A 4.55
307/
037-a
1 308
N
ti
N
S
Pyridin-3-ylmethyl-(3-thiophen-3-
yl-imidazo[1,2-b]pyridazin-6-yI)-
amine
KE1322- 3.32 N A 4.8
324/
038-a 325
S
(3-Imidazol-1-yl-propy1)-(3-thiophen-
3-yl-imidazo[1,2-b]pyridazin-6-yI)-
amine

CA 02620534 2008-02-28
SRG/US/53343 - 52 -
ALJ/TDS
'
KE1322- 3.33 -,r..,-.N A 7.29
324/
039-a
325
A, ,t:Iti
= HI'll N --.._
F \ S
(4-Fluoro-benzyI)-(3-thiophen-3-yl-
imidazo[1,2-131pyridazin-6-y1)-amine
KE1322- 3.34 ,,Cr.N A 8.26 312/
040-a
313
N....t
. O'N Isl-
i
H .....
\ S
Cyclohexylmethyl-(3-thiophen-3-yl-
imidazo(1,2-131pyridazin-6-y1)-amine
KE1322- 3.35N A 7.37
342/
)
F fr-
041-a
343
N N..Ntl
F \ S
(2,4-Difluoro-benzyI)-(3-thiophen-3-
yl-imidazo[1,2-b]pyridazin-6-yI)-
amine
KE1322- 3.36 i.....1,N A 5.31
338/
042-a
339
,1?%Iti
N N
isl-- '
H \ S
[345-Methy1-1H-pyrazol-4-y1)-
propyl]-(3-thiophen-3-yl-imidazo-
, [1,2-b]pyridazin-6-yI)-amine
,
'
KE1322- 3.37 H 0 . A 4.71 328/
043-a /N--f
329
\.....N.) r-Th...- ..,N
NN"Isi".ti
A,
\ s
1-[2-(3-Thiophen-3-yl-imidazo-
[1,2-1Apyridazin-6-ylamino)-ethyl]-
imidazolidin-2-one

CA 02620534 2008-02-28
SRG/US/53343 - 53 -
ALJ/TDS
'
KE1322- 3.38A 4.64
329/
045-a 0-Th
330
1õN.)r....N
CNN-N...t
H-...._
\ S
(2-Morpholin-4-yl-ethyl)-(3-
thiophen-3-yl-imidazo[1,2-13]
pyridazin-6-yI)-amine
KE1322- 3.39A 5.42
358/
046-a .%) Kr-,,,. ,N
359
.N.,^J., A- A4-1
N NN(
H -,
\ S
N*1*,N*1*-Diethyl-N*4*-(34hiophen-
3-yl-imidazo[1,2-13]pyridazin-6-y1)-
pentane-1,4-diamine
KE1322- 3.40N rj A 4.92
329/
047-a
330
N r.:.,...-
11-..t
-=N N-
4
) 1
H ....,
\ S
N,N-Diethyl-W-(3-thiophen-3-yl-
imidazo[1,2-b]pyridazin-6-yI)-
propane-1,3-diamine
KE1322- 3.41 A 4.74
313/ 314
048-a c-IN riy...N
Cfsl-N-Nti
,
1 \ S
(2-Pyrrolidin-1-yl-ethyl)-(3-
thiophen-3-yl-imidazo[1,2-13]-
, pyridazin-6-yI)-amine
HU6083- 3.42ri...,,.. N B 7.99 359.43 /
002 N
N -N,N / 360.06/
I
*9
[3-(3-Methoxy-phenyl)-imidazo[1,2-b
]pyridazin-6-y1j-methyl-(2-pyridin-
2-yl-etbyI)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 54 -
ALJTIDS
=
HU6083- 3.43 9.42
413.40 /
003
413.99
'*O
r F
Methyl-(2-pyridin-2-yl-ethyl)-[3-(3
-trifluoromethoxy-phenyl)-imidazo[1
,2-1Apyridazin-6-01-amine
HU6083- 3.44 N B 10.03
398.30 /
004N N N
397.94
CI
CI
[3-(3,4-Dichloro-phenyl)-imidazo[1,
2-1Apyridazin-6-yli-methyl-(2-pyrid
in-2-yl-ethyl)-amine
HU6083- 3.45 9.16
381.84 /
006N
N NN381.95
CI
[3-(3-Chloro-4-fluoro-phenyl)-imida
zo[1,2-1Apyridazin-6-y1Fmethyl-(2-
pyridin-2-yl-ethyl)-amine
HU6083- 3.46 9.32
379.46 /
007N NN
380.02
AIL
Methyl-(3-naphthalen-2-yl-imidazo[1
,2-13]pyridazin-6-y1)-(2-pyridin-2-y
1-ethyl)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 55 -
ALJ/TDS
HU6083- 3.47 7.47
345.40 / 346.
010/
141 N N"
IP 0
1
[3-(3-Methoxy-phenyI)-imidazo[1,2-b
]pyridazin-6-yI]-(2-pyridin-2-yl-et
hyl)-amine
HU6083- 3.48N B 9.21
384.27 /
N NNN 012 ONõ/- f:Nr-/
383.94
CI
CI
[3-(3,4-Dichloro-phenyl)-imidazo[1,
2-14pyridazin-6-y1]-(2-pyridin-2-y1
-ethyl)-amine
HU6083- 3.49 7.30
340.39 /
013
N NN341.06
3-[6-(2-Pyridin-2-yl-ethylamino)-im
idazo[1,2-b]pyridazin-3-yq-benzoni
bile
HU6083- 3.50f r N 8.84
363.85 /
)
017
N
363.97
410 CI
[3-(3-Chloro-pheny1)-imidazo[1,2-13]
pyridazin-6-y1]-(2-(6-methyl-pyridi
n-2-y1)-ethyl]-amine

CA 02620534 2008-02-28
SRG/US/53343 - 56 -
ALJ/TDS
=
HU6083- 3.51 knõ:õ.-N 9.24
413.40/
019 N N NN
413.99
= 0
A-F
F F
[2-(6-Methyl-pyridin-2-y1)-ethyl]-[
3-(3-trifluoromethoxy-phenyl)-imida
zo[1,2-131pyridazin-6-y1Famine
HU6083- 3.529.15
379.46/
I n N
023
N
380.02
[2-(6-Methyl-pyridin-2-y1)-ethyl]-(
3-naphthalen-2-yl-imidazo[1,2-b]pyr
idazin-6-yI)-amine
HU6083- 3.53 B 9.76
398.30 /
036 397.94
,N
N N N
= CI
CI
[3-(3,4-Dichloro-phenyl)-imidazo[1,
2-b]pyridazin-6-yI]-[2-(4-methyl-py
ridin-2-y1)-ethyl]amine
HU6083- 3.54 B 9.15
379.46 /
039
380.02
N N
[2-(4-Methyl-pyridin-2-y1)-ethyl]-(
3-naphthalen-2-yl-imidazo[1,2-13]pyr
idazin-6-yI)-amine

CA 02620534 2008-02-28
SRG/US/53343 -57-
ALJ/TDS
HU6083- 3.55 9.36
413.40I
067
N 14,N 413.93
0
F F
[2-(3-Methyl-pyridin-2-y1)-ethyl]-[
3-(3-trifluoromethoxy-phenyl)-imida
zo(1,2-b]pyridazin-6-y1]-amine
HU6108- 3.56 N B 8.13
359.43 /
I
058
N
N NN359.17
0
[3-(3-Methoxy-pheny1)-imidazo[1,2-b
jpyridazin-6-y1]-[2-(5-methyl-pyrid
in-2-y1)-ethyl]-amine
HU6108- 3.57 9.49
413.40/
059 N NN
413.15
0
F
[2-(5-Methyl-pyridin-2-y1)-ethyl]-[
3-(3-trifluoromethoxy-phenyl)-imida
zo[1,2-b]pyridazin-6-y1Famine
HU6108- 3.58
10.11 398.30/
060 I N NN
397.94
110 CI
CI
[3-(3,4-Dichloro-phenyl)-imidazo[1,
2-b]pyridazin-6-y1]-(2-(5-methyl-py
ridin-2-y1)-ethyl]amine

CA 02620534 2008-02-28
SRG/US/53343 - 58 -
ALJ/TDS
=
HU6108- 3.59 9.24
381.84/
062
C)\/ /
381.12
HU6108- 3.60 N B 10.16
398.30I
068cCX 397.09 =I
NN""
= CI
CI
[3-(3,4-Dichloro-phenyl)-imidazo[1,
2-b]pyridazin-6-y1H2-(3-methyl-py
ridin-2-y1)-ethyl]amine
HU6083- 3.61 N B 9.79
398.30 /
020
397.94
ci
CI
[3-(3,4-Dichloro-phenyl)-imidazo[1,
2-1Apyridazin-6-y1H2-(6-methyl-py
ridin-2-y1)-ethyl]amine
HU6083- 3.62
7.62 350.81 /
025
C:NLN N..N351.01
=
CI
[3-(3-Chloro-phenyI)-imidazo[1,2-b]
pyridazin-6-yI]-(2-pyrazin-2-yl-eth
yI)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 59 -
ALJ/TDS
=
HU6083- 3.63 6.88
346.39 /
026 CN N
347.03
N
0
[3-(3-Methoxy-phenyI)-imidazo[1,2-b
]pyridazin-6-yI]-(2-pyrazin-2-yl-et
hyl)-amine
HU6083- 3.64 7.79
368.80 /
030 CN N NN /
368.92
CI
(3-(3-Chloro-4-fluoro-phenyl)-imida
zo(1,2-b]pyridazin-6-yI]-(2-pyrazin
-2-yl-ethyl)-amine
HU6083- 3.65 8.01
366.43 /
031N N N4 ,11 /
366.99
(3-Naphthalen-2-yl-imidazo[1,2-b]py
ridazin-6-yI)-(2-pyrazin-2-yl-ethyl
)-amine
HU6083- 3.66 B 8.78
363.85 /
! 033
363.97
N
CI
[3-(3-Chloro-pheny1)-imidazo[1,2-13]
pyridazin-6-yIH2-(4-methyl-pyridi
n-2-y1)-ethylFamine

CA 02620534 2008-02-28
SRG/US/53343 ¨ 60 ¨
ALJ/TDS
HU6083¨ 3.67 B 9.19
413.40/
035 rreN
413.99
N N
=0
FF
[2-(4-Methyl-pyridin-2-y1)-ethyl]
3-(3-trifluoromethoxy-phenyl)-imida
zo[1,2-b]pyridazin-6-y1Famine
r HU6083¨ 3.68 B 8.92
381.84/
038
381.95
.14 /
N N
'CI
[3-(3-Chloro-4-fluoro-phenyl)-imida
zo[1,2-b]pyridazin-6-y1]-(2-(4-meth
yl-pyridin-2-yI)-ethyl]-amine
HU6083¨ 3.69 7.90
338.80 /
049
NN N / 339.00
CI
[3-(3-Chloro-phenyI)-imidazo[1,2-b]
pyridazin-6-y1]-(2-pyrazol-1-yl-eth
yI)-amine
HU6083- 3.70 N B 7.15
334.38/
r 050
335.02
IP 0
[3-(3-Methoxy-phenyI)-imidazo[1,2-b
]pyridazin-6-y1]-(2-pyrazol-1-yl-et
hyl)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 61 -
ALJ/TDS
HU6083- 3.71 8.37
388.35 /
051 /
338.95
N N
*0
A¨F
F F
(2-Pyrazol-1-yl-ethyl)-(3-(3-triflu
oromethoxy-phenyI)-imidazo[1,2-b]py
ridazin-6-yI]-amine
HU6083- 3.72 8.66
373.25 /
052 N" 114 /
372.90
N N
= CI
CI
[3-(3,4-Dichloro-phenyl)-imidazo[1,
2-13]pyridazin-6-y1]-(2-pyrazol-1-y1
-ethyl)-amine
HU6083- 3.73 6.86
329.37/
053
330.02
N
3-[6-(2-Pyrazol-1-yl-ethylamino)-im
idazo[1,2-13]pyridazin-3-0]-benzoni
trile
HU6083- 3.74
8.04 356.79 /
054
N N N"
356.98
'CI
[3-(3-Chloro-4-fluoro-phenyl)-imida
zo[1,2-1Apyridazin-6-y1]-(2-pyrazol
-1-yl-ethyl)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 62 -
ALJ/TDS
HU6083- 3.75 8.22
354.42 /
055
N
335.05
N N
V14-1,
(3-Naphthalen-2-yl-imidazo[1,2-b]py
ridazin-6-y1)-(2-pyrazol-1-yl-ethyl
)-amine
HU6108- 3.76 B 7.98
402.38/
075
N N N
402.14
410 0
A¨F
F F
[2-(I -Methyl-1 H-imidazol-4-y1)-ethy
1]-[3-(3-trifluoromethoxy-phenyl)
midazo[1,2-1Apyridazin-6-yli-amine
HU6108- 3.77 B 6.65
343.39/
077 4
343.15
N
= N
34642-(I -Methyl-1 H-imidazol-4-y1)
-ethylaminoi-imidazo[1,2-b]pyridazi
n-3-y1}-benzonitrile
HU6108- 3.78 B 7.75
368.44 /
079
N
368.18
116
111-4--W
[2-(I -Methyl-I H-imidazol-4-y1)-ethy
1]-(3-naphthalen-2-yl-imidazo[1,2-b
]pyridazin-6-y1)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 63 -
ALJ7TDS
SG26724- 3.79Nf-2: e\r.N 6.89
339.79 /
N
51-A
339.10
CI
[3-(3-Chloro-phenyI)-imidazo[1,2-b]
pyridazin-6-y1]-(241,2,41triazol-1
-yl-ethyl)-amine
SG26724- 3.80 9.38
363.85 /
53-AN N
363.13
CI
[3-(3-Chloro-pheny1)-imidazo[1,2-b]
pyridazin-611]-methyl-(2-pyridin-2
-yl-ethyl)-amine
Description of the HPLC-MS analysis conditions for the examples listed in
Table 3:
HPLC-MS method A: detection: UV = 254 nm; column: Purospher STAR RP18e,
125x4nrim, 5 pm (Merck KGaA, Darmstadt); eluent: A: H20/0.1 /0 TFA, B:
CH3CN/0.1% TFA, gradient: 5 to 95% B in 10 min; flow rate: 1 ml/min:
HPLC-MS method B: detection: UV = 254 nm; column XBridge C18, RP18e,
150x4.8 mm, 5 pm (Waters); gradient 5-95% acetonitrile (0.1% NH4OH) in water
(0.1% NH4OH/NH4HCO3) (10 min.); flow rate 1.0 ml/min.
Method C: (416-(2-hydroxyethylamino)imidazo[1,244pyridazin-3-yliphenol
(Example 4.0)
fN
,.N
HON N N
Br
OH

CA 02620534 2008-02-28
SRG/US/53343 -64 -
ALJ/TDS
85 mg (0.33 mmol) of 2-(3-bromoimidazo[1,2-b]pyridazin-6-ylamino)ethanol
(Example 1.5), 69 mg (0.5 mmol) of 4-hydroxybenzene boronic acid and 76 mg
(0.066 mmol) of tetrakis(triphenylphosphine)palladium(0) were mixed under
argon
with 3.4 ml of dimethyl glycol and 2 ml of an aqueous NaOH solution (a stock
solution of 190 mg of NaOH in 10 ml of water). The mixture was stirred at 90 C
for
19 hours. After cooling, the mixture was diluted with sat. NaCI solution and
extracted
2x with ethyl acetate. The combined organic phases were washed with sat. NaCI
solution, filtered through a silicone filter (from Whatman) and concentrated.
The
resulting crude product was recrystallized from methanol. 40 mg of the desired
113 product are obtained.
1H-NMR (400 MHz; d6-DMS0): 6 = 3.30 - 3.31 (m, 2H, covered by solvent); 3.61 ¨
3.62 (m, 2H); 4.74 (m, 1H); 6.66 (d, 1H); 6.81 (d, 2H); 6.94 ¨ 6.96 (m, 1H);
7.64 ¨
7.67 (m, 2H); 7.93 (d, 2H); 9.57 (br s, 1H) ppm.
MS (ESI+): m/z = 271 ([M-FH]+). [mol. weight = 270.29].

CA 02620534 2008-02-28
SRG/US/53343 - 65 -
ALJ/TDS
The following are prepared in an analogous manner:
Table 4
Mol. weight
Example
Structure and Name of the main isomers 1H-NMR
No. MS (ES+)
4.1 'NMW 284.32
õN
HN N MS (ES+):
[M+1]+ 285
OH
OH
4164(R)-2-Hydroxy-1-methyl-ethylamino)-
imidazo[1,2-b]pyridazin-3-y11-phenol
4.2 MW 314.35
,.1s1
HN N MS (ES+):
104 0 [M+1]4 315
OH
OH
4464(R)-2-Hydroxy-1-methyl-ethylannino)-
imidazo[1,2-b]pyridazin-3-yI]-2-methoxy-
phenol
4.3 rN
MW:
332.38
MS (ES+)
333
''s:21
2-[3-(4-Methanesuffonyl-phenyl)-
imidazo[1,2-b]pyridazin-6-ylaminol-ethanol
4.4 NN MW:
HO
N N 389.48
MS (ES+)
390
/
HN
N-tert-Butyl-416-(2-hydroxy-ethylamino)-
imidazo[1,2-1D]pyridazin-3-y11-

CA 02620534 2008-02-28
SRG/US/53343 -66-
ALJ/TDS
benzenesulfonamide
4.5 er-N MW:
347.40
MS (ES+)
.%
,..,, NH 348
1.1 S
0
N-1446-(2-Hydroxy-ethylamino)-
imidazo[1,2-b]pyridazin-3-y1]-pheny1}-
methanesulfonamide
4.6
MW:
389.48
=MS (ES+)
S--N
H
0
390
N-tert-Buty1-3-[6-(2-hydroxy-ethylamino)-
imidazo[1,2-b]pyridazin-3-y1]-
benzenesulfonamide
4.7 MW:
332.38
MS (ESI+)
iho
333
2-[3-(3-Methanesulfonyl-phenyI)-
imidazo[1,2-b]pyridazin-6-ylaminoFethanol _
4.8 MW:
/ 300.38
MS (ESI+)
s
301
243-(3-Methylsulfanyl-pheny1)-imidazo[1,2-
b]pyridazin-6-ylaminoFethanol
4.9 (300 MHz; 1:16-DMS0): 6 = MW:
2.93 - 2.98 (m, 2H); 3.49 -
N 354.42
N N 3.56 (m, 2H); 6.39 - 6.40 (m,
1H); 6.61 (d, 1H); 7.15 - 7.19
(m, 1H); 7.24 - 7.28 (m, 1H);
7.34 - 7.36 (m, 1H); 7.43 (d,
1H); 7.64 - 7.68 (m, 1H);
[3-(1H-Indo1-5-y1)-imidazo[1,2-b]pyridazin-
7.70 (d, 1H); 7.74 (s, 1H);
7.76 - 7.79 (m, 1H); 8.39 -6-y1]-(2-pyridin-3-yl-ethyl)-amine
8.41 (m, 2H); 8.50 - 8.51 (m,
1H); 11.16(s, 1H) ppm.

CA 02620534 2008-02-28
SRG/US/53343 -67-
ALJ/TDS
4.10 (400 MHz; d6-DMS0): = MW:
2.94 - 2.98 (m, 2H); 3.55
N N 3.60 (m, 2H); 6.65 (d, 1H); 321.41
7.19 - 7.22 (m, 1H); 7.28
S 7.31 (m, 1H); 7.63 - 7.65 (m,
1H); 7.67 - 7.68 (m, 1H);
(2-Pyridin-3-yl-ethyl)-(3-thiophen-3-yl- 7.70 - 7.74 (m, 2H); 7.85 (s,
imidazo[1,2-Npyridazin-6-y1)-amine 1H); 8.32 - 8.33 (m, 1H);
8.39 - 8.40 (m, 1H); 8.48 -
8.49(m, 1H) ppm.
4.11(400 MHz; d6-DMS0): 5 = MW:
XN/ 2.92 - 2.96 (m, 2H); 3.50 -
N = 333.37
N N 3.55 (m, 2H); 6.69 (d, 1H);
7.09 - 7.13 (m, 1H); 7.27 -
7.30 (m 2H). 7.42 - 7.48 (m,
1H); 7.65 - 7.68 (m, 1H);
[3-(3-Fluoro-pheny1)-imidazo[1,2-
7.75 (d, 1H); 7.96 (s, 1H);
,
b]pyridazin-6-y1]-(2-pyridin-3-yl-ethyl)-
7.97 - 7.99 (m 1H); 8.09 -
8.13 (m, 1H); 8.38 - 8.40 (m,
amine
1H); 8.47 - 8.48 (m, 1H)
ppm.
The following are prepared in an analogous manner:
Table 5:
Retention time Mol. weight/
Char Example
(HPLC, UV MS (HPLC-
, No. No. Structure and Name of the main isomer
254 nm) [min]. MS)
, 229_0 5.0 _________________ r:rri
11 5_0
N N N
057
IPAL
365.44
1114,
(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-y1)-(2-
pyridin-2-yl-ethyl)-amine

CA 02620534 2008-02-28
SRG/US/53343 -68-
ALJ/TDS
229_0 5.1
115_0 /
N N N
160
349.82
Cl
[3-(4-Chloro-pheny1)-imidazo[1,2-13]
pyridazin-6-yI]-(2-pyridin-2-yl-eth
yI)-amine
229_0 5.2
115_0
N N N
167
343.43
[3-(3,4-Dimethyl-phenyl)-imidazo[1,
2-b]pyridazin-6-y1]-(2-pyridin-2-y1
-ethyl)-amine
229_0 5.3
115_0
168
FXF
399.37
. F
(2-Pyridin-2-yl-ethyl)3-(3-trifluoromethoxy-phenyl)-
imidazo[1,2-b]pyridazin-6-y1]-amine
229_0 5.4
231_0
164
367.81
[3-(3-Chloro-4-fluoro-pheny1)-imidazo[1,2-1Apyridazin-
6-y1]-(2-pyridin-3-yl-ethyl)-amine
229_0 5.5
115_0
279
349.82
It CI
[3-(3-Chloro-pheny1)-imidazo[1,2-13]pyridazin-6-y1]-(2-
pyridin-211-ethyl)-amine

CA 02620534 2008-02-28
SRG/US/53343 -69 -
ALJ/TDS
229_0 5.6
231_0
279
349.82
[3-(3-Chloro-phenyl)-imidazo[1,2-b]
pyridazin-6-yI]-(2-pyridin-3-yl-eth
yI)-amine
229_0 5.7
115_0
312
= F
383.38
(2-Pyridin-2-yl-ethy1)13-(3-trifluoromethyl-pheny1)-
imidazo[1,2-1Apyridazin-6-y1]-amine
229_0 5.8 i
115_0
313
333.37
F
[3-(3-Fluoro-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-(2-
pyridin-2-yl-ethyl)-amine
229_0 5.9
115_0
339
= 333.37
[3-(4-Fluoro-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-(2-
1 pyridin-2-yl-ethyl)-amine
! 229_0 5.10
115_0
0111*
345
335.43
[3-(4-Methyl-thiophen-2-yI)-imidazo[1,2-b]pyridazin-6-
y1]-(2-pyridin-2-yl-ethyl)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 70 -
ALJ/TDS
229_0 5.11
240_0
164
360.82
443-(3-Chloro-4-fluoro-pheny1)-imidazo[1,2-
b]pyridazin-6-ylamino]-cyclohexanol
229_0 5.12
115_4
145
110 o 357.42
1-{3-[6-(2-Pyridin-2-yl-ethylamino)-imidazo[1,2-
b]pyridazin-3-y1]-phenylyethanone
229_0 5.13
115_6
488 H0, /
408.48
N 0
N-{3-[6-(2-Pyridin-2-yl-ethylamino)-imidazo[1,2-
b]pyridazin-3-ylypheny1}-methanesulfonannide
229_0 5.14
115_0 /
086
340.39
\\
4-[6-(2-Pyridin-2-yl-ethylarnino)-imidazo[1,2-
Npyridazin-3-A-benzonitrile
229_0 5.15
115_4
139
1110
329.41
(2-Pyridin-2-yl-ethyl)-(3-p-tolyl-imidazo[1,2-
b]pyridazin-6-yI)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 71 -
ALJ/TDS
229_0 5.16
115_0 1
061
315.38
(3-Phenyl-imidazo[1,2-b]pyridazin-6-0)-(2-pyridin-2-
ykethyl)-amine
229_0 5.17
115_0 I /
062
365.44
(3-Naphthalen-1-yl-imidazo[1,2-b]pyridazin-6-y1)-(2-
pyridin-2-yl-ethyl)-amine
229_0 5.18
115_0
I /
073
/ =
355.40
(3-Benzofuran-2-yl-imidazo[1,2-b]pyridazin-6-y1)-(2-
pyridin-2-yl-ethyl)-amine
229_0 5.19
115_0
164
367.81
110
=F
[3-(3-Chloro-4-fluoro-phenyI)-imidazo[1,2-b]pyridazin-
6-y1]-(2-pyridin-2-ykethyl)-amine
229_0 5.20
115_0
076
371.47
(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-
,
y1)-(2-pyridin-2-0-ethyl)-arnine

CA 02620534 2008-02-28
SRG/US/53343 - 72 -
ALSTDS
229_0 5.21
115_0
068
359.39
oJ
(3-Benzo[1,3]dioxo1-5-yl-imidazo[1,2-b]pyridazin-6-y1)-
(2-pyridin-2-yl-ethyl)-amine
229_0 5.22
115_0 Ii I
WNVN
280
345.40
/o
[3-(4-Methoxy-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-
(2-pyridin-2-yl-ethyl)-amine
229_0 5.23
2310_ ,1\1
N N
087
405.46
o
/o
(2-Pyridin-3-yl-ethy1)13-(3,4,5-trimethoxy-pheny1)-
imidazo[1,2-b]pyridazin-6-y1Famine
229_0 5.24
N
231_0
339 N N
H =
333.37
[3-(4-Fluoro-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-(2-
pyridin-3-yl-ethyl)-amine
229_0 5.25
231 0
¨
068 N N
359.39
o
(3-Benzo[1,3]dioxo1-5-yl-imidazo[1,2-blpyridazin-6-y1)-

CA 02620534 2008-02-28
SRG/US/53343 - 73 -
ALJ/TDS
(2-pyridin-3-yl-ethyl)-amine
229_0 5.26
N
231_0
280 N N
345.40
0
[3-(4-Methoxy-pheny1)-imidazo[1,2-1Apyridazin-6-y1]-
(2-pyridin-3-yl-ethyl)-amine
229_0 5.27
231_0
345 N N
S 335.43
[3-(4-Methyl-thiophen-2-y1)-imidazo[1,2-b]pyridazin-6-
y1]-(2-pyridin-3-yl-ethyl)-amine
229_0 5.28
231_0
073 N N
/ 0
355.40
41Ik
(3-Benzofuran-2-yl-imidazo[1,2-b]pyridazin-6-y1)-(2-
.
pyridin-3-yl-ethyl)-amine
i 229_0 5.29
' 231 0 N
N N
.057
111, 365.44
(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-y1)-(2-
pyridin-3-yl-ethyl)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 74-
ALJ/TDS
229_0 5.30
N
076 N N
S
371.47
(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-
y1)-(2-pyridin-3-yl-ethyl)-amine
229_0 5.31
r/. N
231_0
N
061 N N
= 315.38
(3-Phenyl-imidazo[1,2-b]pyridazin-6-y1)-(2-pyridin-3-
yl-ethyl)-amine
229_0 5.32
N
231_0
Na N
160 N N
349.82
[3-(4-Chloro-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-(2-
pyridin-3-yl-ethyl)-amine
229_0 5.33
231_0
N N
1086 N N
= 340.39
4-[6-(2-Pyridin-3-yl-ethylamino)-imidazo[1,2-
b]pyridazin-3-y1Fbenzonitrile
229_0 5.34
231_0
312
F
383.38
F F
(2-Pyridin-3-yl-ethy1)43-(3-trifluoromethyl-pheny1)-
imidazo[1,2-b]pyridazin-6-01-amine

CA 02620534 2008-02-28
SRG/US/53343 - 75 -
ALUTDS
229_0 5.35
231_7
468 N N
319.37
fl\IN
[3-(1-Methy1-1H-pyrazol-3-y1)-imidazo[1,2-b]pyridazin-
6-y1]-(2-pyridin-3-yl-ethyl)-amine
229_0 5.36
Ntj
231_4
= 321.41/320
147 N N
0.67
(negative
S
mode)
(2-Pyridin-3-yl-ethyl)-(3-thiophen-2-yl-imidazo[1,2-
b]pyridazin-6-yI)-am me
229_0 5.37
231_6
=====,
N N
488
= 11
408.48
0
N-(3-[6-(2-Pyridin-3-yl-ethylamino)-imidazo[1,2-
b]pyridazin-3-y1]-phenylymethanesulfonamide
229_0 5.38
144_0
,1=1
339
0:)HN N
308.32
111\
[3-(4-Fluoro-pheny1)-imidazo[1,2-1Apyridazin-6-y11-
furan-2-ylmethyl-amine
229_0 5.39
144_0
061 N
290.33
Furan-2-ylmethyl-(3-phenyl-imidazo[1,2-1Apyridazin-6-
y1)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 76 -
ALJ/TDS
229_0 5.40
144_0
280
0:HN N
320.35
0
Furan-2-ylmethy143-(4-methoxy-pheny1)-imidazo[1,2-
b]pyridazin-6-yll-amine
229_0 5.41
144_0
,N
204
329.36
Furan-2-ylmethyl-[3-(1H-indol-5-y1)-imidazo[1,2-
b]pyridazin-6-y1Famine
229_0 5.42
144_0
\CrNH N-
135 0
333.39
N/
[3-(3-Dimethylamino-phenyI)-imidazo[1,2-b]pyridazin-
6-yll-furan-2-ylmethyl-amine
, 229_0 5.43
1144_4
/
140
\ H
320.35
411P 0\
Furan-2-ylmethyl-[3-(3-methoxy-phenyI)-imidazo[1,2-
bipyridazin-6-y1]-amine
229_0 5.44
144_0
ji
CrN
081 o H
347.38
1
o
N-(3-{6-[(Furan-2-y1methyl)-amino]-imidazo[1,2-

CA 02620534 2008-02-28
SRG/US/53343 -77- A
LJ/TDS
b]pyridazin-3-y1}-phenyl)-acetamide
229_0 5.45
144_0
N-
291 \ 0 H
320.35
OH
(3-{61(Furan-2-ylmethyl)-aminoHmidazo[1,2-
Npyridazin-3-y1}-pheny1)-methanol
229_0 5.46
1144_0
080 N N
306.32
OH
4-{6-[(Furan-2-ylmethyl)-amino]-imidazo[1,2-
b]pyridazin-3-yI}-phenol
229_0 5.47
144_0
284
\ 0 H 306.32
= OH
3-{6-[(Furan-2-ylmethyl)-aminoHmidazo[1,2-
b]pyridazin-3-yI}-phenol
229_0 5.48 e\r--N
144_0
Cr
N N-
1347 o H
o
333.35
NH2
3-{6-[(Furan-2-ylmethyl)-amino]-imidazo[1,2-
b]pyridazin-3-yI}-benzamide
! 229_0 5.49
' 144_6
488 \ 0 H
383.43
o--7/
N-(3-{6-[(Furan-2-ylmethyl)-amino]-imidazo[1,2-
blpyridazin-3-yI}-phenyl)-methanesulfonamide

CA 02620534 2008-02-28
SRG/US/53343 - 78 -
ALJ/TDS
229_0 5.50
144_0
314
\ 0 H
336.35
o\
OH
4-{6-[(Furan-2-ylmethyl)-aminol-imidazo[1,2-
b]pyridazin-3-y1}-2-methoxy-phenol
229_0 5.51 rj\r-N
144_4
Cr-N N-
145 o H
332.36
0
1-(3-{6-[(Furan-2-ylmethyl)-amino]-imidazo[1,2-
b]pyridazin-3-y1}-pheny1)-ethanone
229_0 5.52
144_0
311
OrHN N
321.34
/0
Furan-2-ylmethy143-(6-methoxy-pyridin-3-y1)-
imidazo[1,2-blpyridazin-6-y1]-amine
229_0 5.53
1144_0
071 N N
291.31
Furan-2-ylmethyl-(3-pyridin-3-yl-imidazo[1,2-
b]pyridazin-6-yI)-amine
229_0 5.54
144_0
196 N N
321.34

CA 02620534 2008-02-28
SRG/US/53343 - 79 -
ALJ/TDS
Furan-2-yInnethy143-(5-methoxy-pyridin-3-y1)-
imidazo[1,2-b]pyridazin-6-yli-amine
229_0 5.55
144_0
069
OrHN N
291.31
Furan-2-ylmethyl-(3-pyridin-4-yl-imidazo[1,2-
b]pyridazin-6-yI)-amine
229_0 5.56
N
146_0
079 N
S
366.44
0
[3-(3,4-Dimethoxy-phenyI)-imidazo[1,2-b]pyridazin-6-
ylFthiophen-2-ylmethyl-amine
229_0 5.57
146_0
087 N
S
396.47
'0
0
Thiophen-2-ylmethy143-(3,4,5-trimethoxy-pheny1)-
imidazo[1,2-b]pyridazin-6-y1Famine
229_0 5.58
146_4
N
INJ"
145 s H o
348.43
=
1-(3-{6-[(Thiophen-2-ylmethyl)-amino]-imidazo[1,2-
b]pyridazin-3-01-phenyl)-ethanone

CA 02620534 2008-02-28
SRG/US/53343 - 80 -
ALJ/TDS
229_0 5.59
146_0
N
284
322.39
= OH
3-(6-[(Thiophen-2-ylmethyl)-amino]-imidazo[1,2-
b]pyridazin-3-yI}-phenol
229_0 5.60
146_0
,N
Cy.N N-
196
337.41
0
[3-(5-Methoxy-pyridin-3-y1)-imidazo[1,2-b]pyridazin-6-
y1]-thiophen-2-ylmethyl-amine
229_0 5.61
146_0
285 N
S
336.42
HO
(4-(6-[(Thiophen-2-ylmethyl)-amino]-imidazo[1,2-
b]pyridazin-3-yll-pheny1)-methanol
229_0 5.62
146_0
192 s H
o
393.47
OH
N-(2-Hydroxy-ethyl)-3-{6-[(thiophen-2-ylmethyl)-
amino]-imidazo[1,2-b]pyridazin-3-y1}-benzamide
229_0 5.63
146_0
345
\S H
S
326.45
[3-(4-Methyl-thiophen-2-yI)-imidazo[1,2-b]pyridazin-6-

CA 02620534 2008-02-28
SRG/US/53343 - 81 -
ALJ/TDS
ylj-thiophen-2-ylmethyl-amine
229_0 5.64
146_4
147
S 1.02 312.42/314
S
(3-Thiophen-2-yl-im idazo[1,2-b]pyridazin-6-yI)-
thiophen-2-ylm ethyl-am ine
229_0 5.65
146_0
074
\S H 312.42
S
(3-Thiophen-3-yl-imidazo[1,2-b]pyridazin-6-y1)-
thiophen-2-ylmethyl-amine
229_0 5.66
146_0
311
CisHN N
337.41
0
[3-(6-Methoxy-pyridin-3-y1)-imidazo[1,2-1Apyridazin-6-
ylphiophen-2-ylmethyl-amine
229_U 5.67
146_0
N
. 204
= a
345.43
[3-(1H-Indo1-5-y9-imidazo[1,2-13]pyridazin-6-yli-
thiophen-2-ylmethyl-amine

CA 02620534 2008-02-28
SRG/US/53343 - 82 -
ALJ/TDS
229_0 5.68
146_0
N
135 s H
349.46
N/
[3-(3-Dinnethylamino-phenyl)-innidazo[1,2-b]pyridazin-
6-yli-thiophen-2-ylmethyl-amine
229_0 5.69
146_0
339 N N
324.38
[3-(4-Fluoro-pheny1)-imidazo[1,2-b]pyridazin-6-y11-
thiophen-2-ylmethyl-amine
229_0 5.70
146_7
468 N N
H
310.38
\N,NN
[3-(1-Methy1-1H-pyrazol-4-y1)-innidazo[1,2-13]pyridazin-
6-y11-thiophen-2-ylmethyl-amine
229_0 5.71
146_0
071 N N
CH
307.38
(3-Pyridin-3-yl-imidazo[1,2-b]pyridazin-6-y1)-thiophen-
2-ylmethyl-amine
229_0 5.72
146 0
081 H
363.44
o
N-(346-[(Thiophen-2-ylmethy1)-amino]-imidazo[1,2-
b]pyridazin-3-y1}-pheny1)-acetannide

CA 02620534 2008-02-28
SRG/US/53343 - 83 -
ALJ/TDS
229_0 5.73
146_4
N
140
s H 1.01
336.42/338
= o\
[3-(3-Methoxy-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-
thiophen-2-ylmethyl-amine
229_0 5.74
146_0
080 N
S
322.39
OH
4-{6-[(Thiophen-2-yInnethyl)-amino]-imidazo[1,2-
b]pyridazin-3-yI}-phenol
229_0 5.75
146_0
069
OSN N
307.38
(3-Pyridin-4-yl-imidazo[1,2-b]pyridazin-6-yI)-thiophen-
2-ylmethyl-amine
229_0 5.76
146_0
314
s
=
0\
352.42
OH
2-Methoxy-4-{6-Rthiophen-2-ylmethyl)-aminol-
imidazo[1,2-b]pyridazin-3-y1}-phenol
229_0 5.77
146_0
347 N-
s H
o
349.42
NH2
3-{6-[(Thiophen-2-ylmethyl)-amino]-imidazo[1,2-
1Apyridazin-3-y1}-benzamide

CA 02620534 2008-02-28
SRG/US/53343 - 84 - ALJ/TDS
229_0 5.78
146_6
N N
488 s H
399.50
o=s--_.
//
N-(3-{6-[(Thiophen-2-ylmethyl)--amino]-imidazo[1,2-
Npyridazin-3-y1}-phenyl)-methanesulfonamide
229_0 5.79
146_0
N
140
350.40
OH
0
4-{6-[(Thiophen-2-ylmethyl)-amino]-imidazo[1,2-
b]pyridazin-3-yI}-benzoic acid
229_0 5.80 fr-N
237_4
,N
N
140 H N-
N2 0.62
331.38/332
IF 0\
[3-(3-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-y1F
pyridin-4-ylmethyl-amine
229_0 5.81
237_0 tN /
/%1
168 ii I H
N
3
4111p 85.35.
Pyridin-4-ylmethy143-(3-trifluoromethoxy-phenyl)-
imidazo[1,2-1Apyridazin-6-y11-amine
229_0 5.82
frN
237_0
,N
N-
279 I H
N 335.80
= a
[3-(3-Chloro-pheny1)-imidazo[1,2-13]pyridazin-6-y1]-
pyridin-4-ylmethyl-amine

CA 02620534 2008-02-28
SRG/US/53343 - 85 -
ALJ/TDS
229_0 5.83
237_0
õN
312 N
F
369.35
F F
Pyridin-4-ylmethyl-[3-(3-trifluoromethyl-phenyl)-
imidazo[1,2-13]pyridazin-6-y1Famine
229_0 5.84
237_0
164 1jNN
H
N
353.79
CI
[3-(3-Chloro-4-fluoro-pheny1)-imidazo[1,2-b]pyridazin-
6-y1]-pyridin-4-ylmethyl-amine
229_0 5.85
237_0
073
N N
N / 0
341.37
(3-Benzofuran-2-yl-im idazo[1,2-b]pyridazin-6-yI)-
pyriden-4-ylmethyl-am me
229_0 5.86
237_0
õ.4
N
167 I H
N
41,
329.41
[3-(3,4-Dimethyl-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-
pyridin-4-ylmethyl-amine
229_0 5.87
= 237_4
, 139
N N-
H
N
0.66
315.38/316
Pyridin-4-ylmethyl-(3-p-tolyl-imidazo[1,2-b]pyridazin-

CA 02620534 2008-02-28
SRG/US/53343 -86- ALJ/TDS
6-yI)-amine
229_0 5.88
237_4
147
0.61
307.38/308
S
Pyridin-4-ylmethyl-(3-thiophen-2-yl-imidazo[1,2-
b]pyridazin-6-yI)-amine
229_0 5.89
237_0
N
061 N
301.35
(3-Phenyl-imidazo[1,2-lo]pyridazin-6-y1)-pyridin-4-
ylmethyl-amine
229_0 5.90
237 0
,N
N N-
068 H
345.36
= 0
(3-Benzo[1,3]dioxo1-5-yl-imidazo[1,2-b]pyridazin-6-y1)-
pyridin-4-ylmethyl-amine
229_0 5.91
237_0
057 µ11
N
351.41'
(3-Naphthalen-2-yl-imidazo[1,2-1Apyridazin-6-y1)-
pyridin-4-ylmethyl-amine
229_0 5.92
N
237_0
076 rN N
357.44
S

CA 02620534 2008-02-28
SRG/US/53343 - 87 - A
LJ/TD S
(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-
yI)-pyridin-4-ylmethyl-amine
229_0 5.93
237_0
N
160 rN N
335.80
CI
[3-(4-Chloro-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-
pyridin-4-ylmethyl-amine
229_0 5.94
237_0
N
277 H
NJ
380.25
= Br
[3-(3-Bromo-pheny1)-imidazo[1,2-1Apyridazin-6-yll-
pyridin-4-ylmethyl-amine
229_0 5.95
237_6 N
0
}N%
488 r
N
FN
394.46
¨s,
N-(3-{6-[(Pyridin-4-ylmethyp-amino]-imidazo[1,2-
Npyridazin-3-y1}-phenylymethanesulfonamide
229_0 5.96
237_4
038 N
319.34
[3-(2-Fluoro-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-
pyridin-4-ylmethyl-amine
229_4 5.97
007_0
087
391.43
411 \
0

CA 02620534 2008-02-28
SRG/US/53343 -88-
ALJ/TDS
Pyridin-2-ylmethyl-[3-(3,4,5-trimethoxy-pheny1)-
imidazo[1,2-b]pyridazin-6-y11-annine
229_4 5.98 ji
007_0
339 N N
= 319.34
[3-(4-Fluoro-pheny1)-imidazo[1,2-1Apyridazin-6-y1]-
pyridin-2-ylmethyl-amine
229_4 5.99
N
007_0
073
N N
/ 0
341.37
(3-Benzofuran-2-yl-im idazo[1,2-b]pyridazin-6-yI)-
pyridin-2-ylm ethyl-am ine
229_4 5.100
007_0
N
057
351.41
(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-yI)-
pyridin-2-ylmethyl-amine
229_4 5.101
007_0
311 N N
332.37
0
[3-(6-Methoxy-pyridin-3-yI)-imidazo[1,2-b]pyridazin-6-
ylf-pyridin-2-ylmethyl-amine

CA 02620534 2008-02-28
SRG/US/53343 - 89 -
ALJ/TDS
229_4 5.102
007_0
076
N N
S
357.44
=
(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-
y1)-pyridin-2-ylmethyl-amine
229_4 5.103
007_0 õN
168 N
385.35
it 0 F
Pyridin-2-ylmethyl-[3-(3-trifluoromethoxy-phenyI)-
imidazo[1,2-b]pyridazin-6-yI]-amine
229_4 5.104
007_0
074 N N
307.38
S
Pyridin-2-ylmethyl-(3-thiophen-3-yl-imidazo[1,2-
13]pyridazin-6-y1)-amine
229_4 5.105
007_0
312
csNrN.N..,g1
I H
F
369.35
F F
Pyridin-2-ylmethy143-(3-trifluoromethyl-pheny1)-
imidazo[1,2-1D]pyridazin-6-y1]-amine
229_4 5.106
007_U
135 I H
344.42
N/
[3-(3-Dimethylamino-pheny1)-imidazo[1,2-b]pyridazin-
6-y1]-pyridin-2-ylmethyl-amine

CA 02620534 2008-02-28
SRG/US/53343 - 90 - ALJ/TDS
229_4 5.107
007_0 N
164 I
353.79
CI
[3-(3-Chloro-4-fluoro-phenyl)-im idazo[l ,2-b]pyridazin-
, 6-y1Fpyridin-2-ylm ethyl-amine
229_4 5.108
N
007_0
280 N N
331.38
0
[3-(4-Methoxy-pheny1)-imidazo[1,2-b]pyridazin-6-y11-
pyridin-2-ylmethyl-amine
229_4 5.109
007_0
079
361.40
o\
[3-(3,4-Dimethoxy-phenyI)-imidazo[1,2-b]pyridazin-6-
,
y1}-pyridin-2-ylmethyl-amine
1229_0 5.110
223_0
.õN
314 N
380.83/380
0.93
(negative
o
mode)
OH
416-(3-Chloro-benzylamino)-imidazo[1,2-b]pyridazin-
3-y11-2-methoxy-phenol

CA 02620534 2008-02-28
SRG/US/53343 - 91 -
ALJ/TDS
229_0 5.111
N
223_0
285 N
Cl
364.83
HO
{446-(3-Chloro-benzylannino)-imidazo[1,2-b]pyridazin-
3-y0-phenylymethanol
229_0 5.112
223_0 ci
196 = N
365.82
(3-Chloro-benzy1)-[3-(5-methoxy-pyridin-3-y1)-
imidazo[1,2-b]pyridazin-6-y0-amine
229_0 5.113
223_0 ci
284 (00 [\11 N
=OH 350.81
316-(3-Chloro-benzylamino)-imidazo[1,2-b]pyridazin-
3-y0-phenol
229_0 5.114
223_0
CI
071N N
335.80
\
1
(3-Chloro-benzy1)-(3-pyridin-3-yl-imidazo[1,2-
blpyridazin-6-y1)-amine
229_U 5.115
223_0
349.82/349
005 N
0.92
(negative
NH, mode)
[3-(3-Amino-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-(3-
chloro-benzyl)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 92 -
ALJ/TDS
229_0 5.116
223_0
311 NN
365.82
0
(3-Chloro-benzy1)13-(6-methoxy-pyridin-3-y1)-
imidazo[1,2-b]pyridazin-6-y1Famine
229_0 5.117
223_0
CI
080 N
350.81/350
0.89
(negative
mode)
OH
416-(3-Chloro-benzylamino)-imidazo[1,2-b]pyridazin-
3-y1]-phenol
229_0 5.118
223_0
CI
069 N
335.80
/
(3-Chloro-benzy1)-(3-pyridin-4-yl-imidazo[1,2-
b]pyridazin-6-y1)-amine
229_0 5.119
223_0 ci
. 347N
* o 377.83
NH2
346-(3-Chloro-benzylamino)-imidazo[1,2-b]pyridazin-
3-yI]-benzamide
229_0 5.120
223_0 ci
140 N"
378.82
O
416-(3-Chloro-benzylam ino)-im idazo[01,2-b]pHyridazin-
3-y1i-benzoic acid

CA 02620534 2008-02-28
SRG/US/53343 - 93 - ALJ/TDS
229_0 5.121
224_0
N
069
0.77 319.34/320
(4-Fluoro-benzy1)-(3-pyridin-4-yl-imidazo[1,2-
b]pyridazin-6-y1)-amine
229_0 5.122
224_0
080 N N
0.86 334.35/335
OH
4-[6-(4-Fluoro-benzylamino)-imidazo[1,2-b]pyridazin-
3-y11-phenol
229_0 5.123
224_0
N
196
0.92 349.37/350
\
(4-Fluoro-benzy1)43-(5-methoxy-pyridin-3-y1)-
imidazo[1,2-b]pyridazin-6-y11-amine
229_0 5.124
224_0 /
N
284
334.35
OH
346-(4-Fluoro-benzylamino)-imidazo[1,2-b]pyridazin-
3-y11-phenol
229_0 5.125
224_0
345 N
1.14 338.41/340
(4-Fluoro-benzy1)-[3-(4-methyl-thiophen-2-y1)-
imidazo[1,2-blpyridazin-6-y11-amine

CA 02620534 2008-02-28
SRG/US/53343 - 94 -
ALJ/TDS
229_0 5.126
224_0
.õr1,1
068 H
N
1.02 362.36/363
o
o¨j
(3-Benzo[1,3]dioxo1-5-yl-imidazo[1,2-b]pyridazin-6-y1)-
(4-fluoro-benzyl)-amine
229_0 5.127
, 224_0 N
1204 N
0.96 357.39/358
1
(4-Fluoro-benzy1)43-(1H-indo1-5-y1)-imidazo[1,2-
13]pyridazin-6-y1]-amine
, 229_0 5.128
224_0
280 N N
110 1.04
348.38/349
1 (4-Fluoro-benzy1)-[3-(4-methoxy-pheny1)-imidazo[1,2-
b]pyridazin-6-y1Famine
229_0 5.129
224_0
Fl
N N-
311 =
1.00 349.37/350
0
(4-Fluoro-benzy1)43-(6-methoxy-pyridin-3-y1)-
i imidazo[1,2-b]pyridazin-6-y1Famine
229_0 5.130
224_0 ,N
N-
I 081
0.89 375.41/376
= t
N-{3-(6-(4-Fluoro-benzylamino)-imidazo[1,2-
_

CA 02620534 2008-02-28
SRG/US/53343 - 95 -
ALJ/TDS
b]pyridazin-3-y11-phenylyacetamide
229_0 5.131
224_0
071 N N-
H
0.83 319.34/320
(4-Fluoro-benzy1)-(3-pyridin-3-yl-imidazo[1,2-
b]pyridazin-6-y1)-amine
229_0 5.132
224_0
285 N
0.85 348.38/349
HO
(416-(4-Fluoro-benzylamino)-imidazo[1,2-b]pyridazin-
3-y11-phenylymethanol
229_0 5.133
224_0
347 N
0 361.38
NH2
346-(4-Fluoro-benzylamino)-inn idazo[1,2-b]pyridazin-
3-yl]-benzamide
229_0 5.134 ry-N
224_0
I 140 N
=
362.36
0
HO
4-[6-(4-Fluoro-benzylam ino)-im idazo[1,2-b]pyridazin-
3-y1j-benzoic acid
229_0 5.135 e\r--N
244_4
õ.t1.1
139 hi NI
o
1.06 344.42/345
(4-Methoxy-benzy1)-(3-p-tolyl-imidazo[1,2-13]pyridazin-

CA 02620534 2008-02-28
SRG/US/53343 - 96 -
ALJ/TDS
6-yI)-amine
229_0 5.136
244_0
160 110 N
364.83/364
0 1.13
(negative
mode)
CI
[3-(4-Chloro-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-(4-
methoxy-benzy1)-amine
229_0 5.137
244_0 =
345
350.44/349
0 s 1.09
(negative
mode)
(4-Methoxy-benzy1)13-(4-methyl-thiophen-2-y1)-
imidazo[1,2-blpyridazin-6-y1]-amine
229_0 5.138
244_0 õN
N
204 410
o
It
0.93 369.43/370
[3-(1H-Indo1-5-y1)-imidazo[1,2-blpyridazin-6-y1]-(4-
nnethoxy-benzyl)-amine
229_0 5.139
244_0
N
280 [16 N
0
360.42
0
(4-Methoxy-benzy1)43-(4-methoxy-pheny1)-
innidazo[1,2-b]pyridazin-6-y11-amine
229_0 5.140
244_0
339 N
o
1.04 348.38/349
[3-(4-Fluoro-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-(4-
methoxy-benzyI)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 97 - A LJ/TDS
229_0 5.141 -!%\rõ-N
244_ NN
N
080
o
0.85 346.39/347
OH
416-(4-Methoxy-benzylannino)-imidazo[1,2-
b]pyridazin-3-yli-phenol
229_0 5.142 xjyt2.1
244_7
N
467
o 0.72 320.35/321
õ..NH
(4-Methoxy-benzy1)-[3-(1H-pyrazol-4-y1)-imidazo[1,2-
13]pyridazin-6-y11-arnine
229 0 5.143
24417
468 HN
o 0.82 334.38/335
,N
N
(4-Methoxy-benzy1)43-(1-methyl-1H-pyrazol-4-y1)-
imidazo[1,2-b]pyridazin-6-y1]-amine
229_0 5.144 X\r-N
244_0
(110 N 1\1-'1\j
140
\o
374.40
Flo
446-(4-Methoxy-benzylamino)-imidazo[1,2-
b]pyridazin-3-yli-benzoic acid
;229_6 5.145
307_0
087 H2 40 H
N
0 \ID Ck 469.52
44[3-(3,4,5-Trimethoxy-pheny1)-imidazo[1,2-
blpyridazin-6-ylamino]-methyl}-benzenesulfonamide

CA 02620534 2008-02-28
SRG/US/53343 -98-
ALJ/TDS
229_6 5.146
307_0
3142 H
H ts1
A
* =
425.47
0 0
OH
44[3-(4-Hydroxy-3-methoxy-phenyl)-imidazo[1,2-
Npyridazin-6-ylaminoFmethylybenzenesulfonamide
229_6 5.147
307_0
284
395.44
A H
H2NL
0
4-{[3-(3-Hydroxy-pheny1)-imidazo[1,2-1Apyridazin-6-
ylaminoFmethyl}-benzenesulfonamide
229_6 5.148
307_0
057H 2 N H
0 \0 4116 429.50
4-[(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-
ylamino)-methyll-benzenesulfonamide
229_6 5.149
307_4
139 110 H
H2N,,s
393.47
4-[(3-p-Tolyl-imidazo[1,2-b]pyridazin-6-ylamino)-
methylFbenzenesulfonamide
' 229_6 5.150
307_0
116711¨
H2N>
407.50
44[3-(3,4-Dimethyl-pheny1)-imidazo[1,2-1D]pyridazin-6-
ylaminoFmethyl}-benzenesulfonamide

CA 02620534 2008-02-28
SRG/US/53343 - 99 -
ALJ71-DS
229_6 5.151
307_0
086
H2
o
404.45
0
4-{[3-(4-Cyano-pheny1)-imidazo[1,2-b]pyridazin-6-
ylaminopnethylybenzenesulfonamide
229_6 5.152
307_0
H
1110
312
//
447.44
o \\0
4-{[3-(3-Trifluoromethyl-pheny1)-imidazo[1,2-
b]pyridazin-6-ylaminoi-methylybenzenesulfonamide
229_6 5.153
307_0
204H
H2N,,s
\\
418.48
O o
4-{[3-(1H-Indo1-5-y1)-imidazo[1,2-1Apyridazin-6-
ylaminol-methylybenzenesulfonamide
229_6 5.154
307_0
068 H2Nõ,
H
/7\\
? 423.45
o 0
4-[(3-Benzo[1,3]dioxo1-5-yl-imidazo[1,2-1Apyridazin-6-
ylamino)-methylFbenzenesulfonamide
229 6 5.155
307_0
164 H2N 410 H
431.88
O 0 it a
4-{[3-(3-Chloro-4-fluoro-pheny1)-imidazo[1,2-
19]pyridazin-6-ylaminoFmethyll-benzenesulfonamide

CA 02620534 2008-02-28
SRG/US/53343 - 100 -
ALJ/TDS
229_6 5.156
307_0 110
168 H2N
463.44
0 0 LF
4-{[3-(3-Trifluoromethoxy-pheny1)-imidazo[1,2-
b]pyridazin-6-ylaminol-methylybenzenesulfonamide
229_6 5.157
307_0
2 40 H
280 H
411 409.47
0 0
4-{[3-(4-Methoxy-phenyI)-imidazo[1,2-b]pyridazin-6-
ylaminoFmethylybenzenesulfonamide
229_6 5.158
307_0
41
080 0
H2N'A 1111 H
0 0 395.44
OH
4-{[3-(4-Hydroxy-phenyl)-imidazo[1,
2-1Apyridazin-6-ylanninoFmethyl)-be
nzenesulfonamide
229_6 5.159
307_0
H
291 H,Nõ_
409.47
0 0
OH
4-0-(3-Hydroxymethyl-pheny1)-im id
azo[1,2-b]pyridazin-6-ylaminoi-meth
y1}-benzenesulfonamide
229_6 5.160
307_4
H
145 H2 1\1::A\
0
421.48
0
4-{[3-(3-Acetyl-pheny1)-imidazo[1,2-13]pyridazin-6-
ylaminopnethylybenzenesulfonamide

CA 02620534 2008-02-28
SRG/US/53343 - 101 -
ALJ/TDS
229_6 5.161
307_7
110 H
468 H2
383.43
0 0 ----NN
4-{[3-(1-Methy1-1H-pyrazol-4-y1)-imidazo[1,2-
b]pyridazin-6-ylaminoRnethylybenzenesulfonamide
229_0 5.162
227_0 a 40 001.
087
ck 1.14 459.33 / 461
/0
(3,4-Dichloro-benzy1)43-(3,4,5-trimethoxy-pheny1)-
imidazo[1,2-b]pyridazin-6-y1]-amine
229_0 5.163
227_0 a /
io N
080 Ci
385.25
OH
446-(3,4-Dichloro-benzylamino)-innidazo[1,2-
b]pyridazin-3-yll-phenol
229_0 5.164
227_0 c,
280
399.28
/0
(3,4-Dichloro-benzy1)43-(4-methoxy-pheny1)-
imidazo[1,2-b]pyridazin-6-y1Famine
229_0 5.165
227_0
311 110
400.27
/0
(3,4-Dichloro-benzy1)13-(6-methoxy-pyridin-3-y1)-
imidazo[1,2-b]pyridazin-6-yll-amine
229_0 5.166
227_0 ciio
204
CI
408.29
(3,4-Dichloro-benzy1)-[3-(1H-indo1-5-y1)-imidazo[1,2-
b]pyridazin-6-y1Famine

CA 02620534 2008-02-28
SRG/US/53343 - 102 -
ALJ/TDS
229_U 5.167
40.
227_0 c
140
CI 110
413.26
=
HO
416-(3,4-Dichloro-benzylamino)-im idazo[1,2-
bjpyridazin-3-y11-benzoic acid
229_0 5.168
236_0 =
069 <
=
0.74 345.36/346
Benzo[1,3]dioxo1-5-ylmethyl-(3-pyridin-4-yl-
imiclazo[1,2-b]pyridazin-6-y1)-amine
229_0 5.169
236_0
314AI< , = 390.40
=
OH
4-{6-[(Benzo[1,3]dioxo1-5-ylmethyl)-amino]-
imidazo[1,2-b]pyridazin-3-y1}-2-nnethoxy-phenol
229_0 5.170
236_0
280 <6 1. H
=
0.97 374.40/375
Benzo[1,3]dioxo1-5-ylmethy143-(4-methoxy-pheny1)-
imidazo[1,2-Npyridazin-6-yli-amine
229 0 5.171
236_0
H
=
311 0 /
0.95 375.39/376
/0
Benzo[1,3]dioxo1-5-yInnethy143-(6-methoxy-pyridin-3-
y1)-imidazo[1,2-b]pyridazin-6-y1Famine
229_0 5.172
=
236_0 41040
080< H
=
0.83 360.37/361
= H
4-{6-[(Benzo[1,3]clioxol-5-ylmethyl)-aminol-
imidazo[1,2-b]pyridazin-3-y1)-phenol

CA 02620534 2008-02-28
SRG/US/53343 - 103 -
ALJ/TDS
229_0 5.173
236_0 = 40.
284< H
0 4 OH 0.87
360.37/361 11
3-{6-[(Benzo[1,3]dioxo1-5-ylmethyl)-amino]-
imidazo[1,2-b]pyridazin-3-y1}-phenol
229_0 5.174
1236_7 =
! 468 <
0
0.79
348.36/349
Benzo[1,3]clioxo1-5-ylmethyl-[3-(1-methyl-1H-pyrazol-
4-y0-imidazo[1,2-1Apyridazin-6-y1Famine
229_0 5.175
236_0 =
140 <
0
388.38
HO
4-{6-[(Benzo[1,3]dioxo1-5-ylmethyl)-aminoj-
imidazo[1,2-b]pyridazin-3-y1}-benzoic acid
229_0 5.176
236_6 =
488 < H
411, H
437.48
17-
N-(3-{61(Benzo[1,3]dioxo1-5-ylmethyl)-aminot-
imidazo[1,2-b]pyridazin-3-y1)-phenyly
methanesulfonamide
229_0 5.177
236_0 = 40.
347 <
=
= o
387.40
NH,
3-{61(Benzo[1,3]dioxo1-5-ylmethyl)-amino]-
imidazo[1,2-b]pyridazin-3-ylybenzamide
229 0 5.178
1033_0
087
*
0.84 358.40/359
¨0 0
(2-Methoxy-ethy1)13-(3,4,5-trimethoxy-phenyl)-
imidazo[1,2-Npyridazin-6-y11-amine

CA 02620534 2008-02-28
SRG/US/53343 - 104-
ALJ/TDS
229_0 5.179
033_0 N /
284
o
284.32
(2-Methoxy-ethyl)-[3-(3-methoxy-pheny1)-im idazo[1,2-
b]pyridazin-6-y1Fam ine
229_0 5.180
033_0
314
* o
314.34
OH
2-Methoxy-446-(2-methoxy-ethylamino)-imidazo[1,2-
b]pyridazin-3-yl]-phenol
229_U 5.181
033_0
196 /
299.33
0\
(2-Methoxy-ethy1)-[3-(5-methoxy-pyridin-3-y1)-
imidazo[1,2-b]pyridazin-6-yli-amine
229_0 5.182
033_0
057
*AL 1.00
318.38/319
(2-Methoxy-ethyl)-(3-naphthalen-2-yl-imidazo[1,2-
13]pyridazin-6-y1)-amine
, 229_0 5.183
00.
10330
1311 =
/
299.33
0
(2-Methoxy-ethy1)13-(6-methoxy-pyridin-3-y1)-
imidazo[1,2-b]pyridazin-6-y1Famine
229_0 5.184
033_0 110.
324.41/323
076
1.07 (negative
mode)
(3-Benzo[b]thiophen-2-yl-im idazo[1,2-b]pyridazin-6-
y1)-(2-methoxy-ethyl)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 105 -
ALJ/TDS
=
229_0 5.185
033_0
160
302.76
[3-(4-Chloro-pheny1)-imidazo[1,2-1Apyridazin-6-y1]-(2-
methoxy-ethyl)-amine
229_0 5.186
033_0 /
280
0.84 298.34/299
0
(2-Methoxy-ethyl)-[3-(4-methoxy-pheny1)-imidazo[1,2-
b]pyridazin-6-y1Famine
229_0 5.187
033_0 401.
068
? 312.33
(3-Benzo[1,3]dioxo1-5-yl-imidazo[1,2-b]pyridazin-6-y1)-
(2-methoxy-ethyl)-amine
229_0 5.188
033_0
312 411 F 1.02
336.32/337
F F
(2-Methoxy-ethy1)13-(3-trifluoromethyl-phenyl)-
imidazo[1,2-Npyridazin-6-yli-amine
, 229_0 5.189
033_0 00. =
081 * 0.71
325.37/326
N-{346-(2-Methoxy-ethylamino)-imidazo[1,2-
Npyridazin-3-y1]-phenylyacetamide
229_0 5.190
033_0
168
0 F 1.05 352.32/353
(2-Methoxy-ethyl)-13-(3-trifluoromethoxy-pheny1)-
imidazo[1,2-Npyridazin-6-y1Famine

CA 02620534 2008-02-28
SRG/US/53343 - 106 -
ALJ/TDS
229_0 5.191
033_0 410.
204
0.78 307.36/308
\ NH
[3-(1H-Indo1-5-y1)-imidazo[1,2-b]pyridazin-6-y1]-(2-
methoxy-ethyl)-amine
229_0 5.192
033_0 /
279 302.76
a
[3-(3-Chloro-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-(2-
methoxy-ethyl)-amine
229_0 5.193
033_0 /
345 0.92
288.37/289
(2-Methoxy-ethy1)43-(4-methyl-thiophen-2-0)-
imidazo[1,2-b]pyridazin-6-y1Famine
229_0 5.194
033_0 /
080
0.68 284.32/285
OH
4-[6-(2-Methoxy-ethylamino)-imidazo[1,2-b]pyridazin-
3-y1]-phenol
229_0 5.195
033_0
285
0.67 298.34/299
HO
(416-(2-Methoxy-ethylamino)-imidazo[1,2-b]pyridazin-
3-yll-phenylymethanol
229_0 5.196
033_4 1411111t
140
1110, 0 0.86
298.34/299
(2-Methoxy-ethy1)43-(3-methoxy-pheny1)-imidazo[1,2-
1D]pyridazin-6-y1Famine

CA 02620534 2008-02-28
SRG/US/53343 - 107 -
AL-171-DS
229_0 5.197
033_0
277 Br
347.22
4111
[3-(3-Bromo-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-(2-
methoxy-ethyl)-amine
229_0 5.198
033_0 /
140
411
312.33
0
HO
4-[6-(2-Methoxy-ethylamino)-imidazo[1,2-1Apyridazin-
3-yq-benzoic acid
229_0 5.199
, 033_0
347 11 0
311.34
NH,
346-(2-Methoxy-ethylamino)-imidazo[1,2-b]pyridazin-
3-yll-benzamide
229_0 5.200
033_6
488
*
361.42
0
N-{346-(2-Methoxy-ethylamino)-imidazo[1,2-
1Apyridazin-3-yli-phenylymethanesulfonamide
229_0 5.201
033_7
=
469
N
348.41
[3-(1-Benzy1-1H-pyrazol-4-y1)-imidazo[1,2-1Apyridazin-
6-y1]-(2-methoxy-ethyl)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 108 - ALJ/TDS
229_0 5.202
033_0 N /
079
It 0
328.37
0
[3-(3,4-Dirnethoxy-pheny1)-imidazo[1,2-1Apyridazin-6-
,
y1]-(2-methoxy-ethyl)-amine
229_0 5.203
033_4
1145 0
310.36
1-{346-(2-Methoxy-ethylamino)-imidazo[1,2-
,
b]pyridazin-3-y1)-phenylyethanone
229_0 5.204
248_0 HO
087
di. 0 0.76
358.40/359
¨0 0
3-[3-(3,4,5-Trimethoxy-phenyI)-imidazo[1,2-
b]pyridazin-6-ylaminoj-propan-1-ol
229_0 5.205
õ 248_0 HO
314
it 0
314.34
OH
446-(3-Hydroxy-propylamino)-imidazo[1,2-
lApyridazin-3-y11-2-methoxy-phenol
1229_0 5.206
I 248 0 40*
I ¨ HO
! 277 = Br
347.22
343-(3-Bronno-pheny1)-imidazo[1,2-b]pyridazin-6-
ylaminoFpropan-1-ol
229_0 5.207
248_0 HO \
079
it 0 0.73
328.37/329
0
343-(3,4-Dimethoxy-pheny1)-imidazo[1,2-b]pyridazin-
6-ylaminoFpropan-1-ol

CA 02620534 2008-02-28
SRG/US/53343 - 109 -
ALJ/TDS
229_0 5.208
248_0 HON
312
F
336.32
F F
313-(3-Trifluoromethyl-pheny1)-imidazo[1,2-
b]pyridazin-6-ylaminoi-propan-1-ol
229_0 5.209
248_7 HO
468
272.31
N
3-[3-(1-Methy1-1H-pyrazol-4-y1)-imidazo[1,2-
b]pyridazin-6-ylaminoypropan-1-ol
229_0 5.210
248_0 HO
168
41 0 F 352.32
Y"--F
3-[3-(3-Trifluoromethoxy-phenyl)-im idazo[1,2-
b]pyridazin-6-ylaminoypropan-1-ol
229_0 5.211
248_0 HO
345 s
288.37
343-(4-Methyl-thiophen-2-y1)-imidazo[1,2-b]pyridazin-
6-ylaminol-propan-1-ol
229_0 5.212
248_0 HO
057
=
*AL 0.90 318.38/319
3-(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-
ylamino)-propan-1-ol
229_0 5.213
248_4
HO
139
0.79 282.35/283
3-(3-p-Tolyl-imidazo[1,2-b]pyridazin-6-ylamino)-
propan-1-ol

CA 02620534 2008-02-28
SRG/US/53343 -110-
ALJ/TDS
229_0 5.214
248_0 HO
074 0.72
274.35/275
\ s
3-(3-Thiophen-3-yl-imidazo[1,2-b]pyridazin-6-
ylamino)-propan-l-ol
229_0 5.215
248_0 HO
076 i
0.94 324.41/325
3-(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-
ylamino)-propan-1-ol
229_0 5.216
248_0 HO 4sj
311 /
0.69 299.33/300
0
3-[3-(6-Methoxy-pyridin-3-y1)-imidazo[1,2-1Apyridazin-
6-ylaminoFpropan-1-ol
229_0 5.217
248_0 HO
204
071
.
307.36/308
\ NH
3-[3-(1H-Indo1-5-y1)-imidazo[1,2-1Apyridazin-6-
ylamino]-propan-1-ol
229_0 5.218
248_0
, 280
0.75 298.34/299
0
3-[3-(4-Methoxy-phenyI)-imidazo[1,2-b]pyridazin-6-
ylamino]-propan-1-ol
229_0 5.219
248_0 HO
164
c, 320.75
3-[3-(3-Chloro-4-fluoro-pheny1)-imidazo[1,2-
b]pyridazin-6-ylaminoFpropan-1-ol

CA 02620534 2008-02-28
SRG/US/53343 - 111 -
ALJ/TDS
229_0 5.220
248_0 HO
279
302.76
411
3-[3-(3-Chloro-pheny1)-imidazo[1,2-b]pyridazin-6-
ylaminoFpropan-1-ol
229_0 5.221
' 248_6
488
361.42
0
N-{316-(3-Hydroxy-propylamino)-imidazo[1,2-
1Apyridazin-3-yli-phenylymethanesulfonamide
229_0 5.222
' 248_7 HO
469
\rsr¨N
348.41
3-[3-(1-Benzy1-1H-pyrazol-4-y1)-imidazo[1,2-
131pyridazin-6-ylamino]-propan-1-01
229_0 5.223
248_0 HO
135 = N/ 311.39
313-(3-Dimethylamino-pheny1)-imidazo[1,2-
b]pyridazin-6-ylamino]-propan-1-ol
229_0 5.224
1248_0 HO
1062
318.38
3-(3-Naphthalen-1-yl-irnidazo[1,2-Npyridazin-6-
ylamino)-propan-1-ol
229_0 5.225
1226_0 /
1087
0 0.94
342.40/343
--0
0
Propyl-[3-(3,4,5-trimethoxy-pheny1)-imidazo[1,2-
' __
b]pyridazin-6-y1Famine

CA 02620534 2008-02-28
SRG/US/53343 - 112 -
ALJ/TDS
229_0 5.226
226_0
314
0 0.81
298.34/299
OH
2-Methoxy-4-(6-propylarnino-imidazo[1,2-b]pyridazin-
3-y1)-phenol
229_0 5.227
226_0 40.
079
411 0 0.91
312.37/313
0¨
, [3-(3,4-Dimethoxy-pheny1)-imidazo[1,2-1Apyridazin-6-
y1]-propyl-amine
229_0 5.228
226_0 etik
204
291.36
\ NH
[3-(1H-Indo1-5-y1)-imidazo[1,2-1Apyridazin-6-y1Fpropyl-
amine
' 229_0 5.229
226_4 01.
140
o 282.35
[3-(3-Methoxy-pheny1)-imidazo[1,2-b]pyridazin-6-y11-
, propyl-amine
1229_0 5.230
226_0 .
1 081
0.80
309.37/310
0
N-[3-(6-Propylamino-imidazo[1,2-Npyridazin-3-y1)-
1
phenylFacetamide
229_0 5.231
226_0
1168
o
1.18 336.32/337
FF
Propyl-[3-(3-trifluoromethoxy-phenyI)-imidazo[1,2-
b]pyridazin-6-yI]-amine

CA 02620534 2008-02-28
SRG/US/53343 - 113 - A
LJ/TDS
229_0 5.232
226_0
280
0.96 282.35/283
0
[3-(4-Methoxy-pheny1)-imidazo[1,2-b]pyridazin-6-y11-
propyl-amine
229_0 5.233
226_0
074 0.95
258.35/259
\ s
Propyl-(3-th iophen-3-yl-im idazo[1,2-b]pyridazin-6-y1)-
amine
229_U 5.234
226_0
345 1.06
272.37/273
[3-(4-Methyl-thiophen-2-y1)-imidazo[1,2-1Apyridazin-6-
y1Fpropyl-amine
229_0 5.235
226_0
071 / 0.73
253.31/254
Propyl-(3-pyridin-3-yl-im idazo[1,2-b]pyridazin-6-yI)-
amine
229_0 5.236
226_0
311
\N
0.91 283.33/284
/0
[3-(6-Methoxy-pyridin-3-yI)-imidazo
[1,2-1Apyridazin-6-y1Fpropyl-amine
229_0 5.237
226_0
080
411 0.78
268.32/269
OH
4-(6-Propylamino-imidazo[1,2-Npyridazin-3-y1)-phenol

CA 02620534 2008-02-28
SRG/US/53343 - 114 -
ALJ/TDS
229_0 5.238
226_0
068
? 0.94
296.33/297
(3-Benzo[1,3]dioxo1-5-yl-imidazo[1,2-b]pyridazin-6-y1)-
propyl-amine
229_0 5.239
226_0
291
0.81 282.35/283
OH
[3-(6-Propylamino-imidazo[1,2-b]pyridazin-3-y1)-
pheny1]-methanol
229_0 5.240
226_0
140
296.33
0
HO
4-(6-Propylamino-imidazo[1,2-b]pyridazin-3-yI)-
benzoic acid
229_0 5.241
226_0
347 * 0
295.34
NH2
3-(6-Propylamino-imidazo[1,2-b]pyridazin-3-yI)-
benzamide
229_0 5.242
226_0 Orik
135 * N/ 295.39
[3-(3-Dimethylamino-phenyl)-innidazo[1,2-b]pyridazin-
6-y1Fpropyl-amine
229_0 5.243
226_0
268.32
284
OH
3-(6-Propylamino-imidazo[1,2-b]pyridazin-3-yI)-phenol

CA 02620534 2008-02-28
SRG/US/53343 - 115 -
ALJ/TDS
229_0 5.244
226_0 Orak
005
267.33
11
NH2
[3-(3-Amino-pheny1)-imidazo[1,2-b]pyridazin-6-y11-
propyl-amine
229_0 5.245
226_0 11111*
1333
267.33
NH2
[3-(4-Amino-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-
propyl-amine
229_0 5.246
226_0
004
Alt
295.39
N
[3-(4-Dimethylamino-pheny1)-imidazo[1,2-b]pyridazin-
6-y11-propyl-amine
229_0 5.247
226_0
285
282.35
HO
[4-(6-Propylamino-imidazo[1,2-b]pyridazin-3-yI)-
phenyTmethanol
229_0 5.248
226_0
11 196 /
283.33
[3-(5-Methoxy-pyridin-3-y1)-imidazo[1,2-b]pyridazin-6-
y1]-propyl-amine
229_4 5.249
016_4
139
295.39
N,N-Dimethyl-N'-(3-p-tolyl-imidazo[1,2-b]pyridazin-6-
, yl)-ethane-1,2-diamine

CA 02620534 2008-02-28
SRG/US/53343 - 116 -
ALJ/TDS
229_4 5.250
016_0
073 / 0
0.78
321.38/322
11111
N'-(3-Benzofuran-2-yl-imidazo[1,2-b]pyridazin-6-yI)-
N,N-dimethyl-ethane-1,2-diamine
229_4 5.251
016_0
074
287.39
\ s
N,N-Dimethyl-N'-(3-thiophen-3-yl-imidazo[1,2-
b]pyridazin-6-yI)-ethane-1,2-diamine
1229_4 5.252
016_0
057
*At 331.42
N,N-Dimethyl-N-(3-naphthalen-2-yl-imidazo[1,2-
b]pyridazin-6-y1)-ethane-1,2-diannine
229_4 5.253
016_0
076 s
337.45
411
N'-(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-
' 6-yI)-N,N-dimethyl-ethane-1,2-diamine
229_4 5.254
410*
1016 0
, 079
341.41
0
N'-[3-(3,4-Dimethoxy-pheny1)-imidazo[1,2-b]pyridazin-
6-y1]-N,N-dimethyl-ethane-1,2-diamine
229_4 5.255
016_0
339
299.35
N'43-(4-Fluoro-pheny1)-imidazo[1,2-1Apyridazin-6-y11-
N,N-dimethyl-ethane-1,2-diamine

CA 02620534 2008-02-28
SRG/US/53343 - 117 -
ALJ/TDS
229_4 5.256
1
016_0
279
315.81
ci
N'43-(3-Chloro-pheny1)-imidazo[1,2-1Apyridazin-6-y1]-
N,N-dimethyl-ethane-1,2-diamine
229_0 5.257
254_0 HN
087 Li =0/
386.45
0\
(S)-3-Methy1-243-(3,4,5-trimethoxy-pheny1)-
imidazo[1,2-1Apyridazin-6-ylaminol-butan-1-ol
229_0 5.258
254_0
HN
3141 0/
342.40
H 'W'
OH
4464(S)-1-Hydroxymethy1-2-methyl-propylamino)-
imidazo[1,2-b]pyridazin-3-y1]-2-methoxy-phenol
229_0 5.259
254_0
HN
079 Li IP 0/
356.42
(S)-213-(3,4-Dimethoxy-pheny1)-imidazo[1,2-
1Apyridazin-6-ylamino]-3-methyl-butan-1-ol
229 0 5.260
1254_0
HN
! 284Y 312.37 OH
3-[6-((S)-1-Hydroxymethy1-2-nnethyl-propylamino)-
imidazo[1,2-b]pyridazin-3-y1]-phenol
229_0 5.261
254_0
HN
080 YL1H
312.37
OH
4-[6-((S)-1-Hydroxymethy1-2-methyl-propylamino)-
imidazo[1,2-b]pyridazin-3-01-phenol

CA 02620534 2008-02-28
SRG/US/53343 - 1 1 8 -
ALJ/TDS
229_0 5.262
254_0 /
HN
285 \.))
326.40
OH
HO
(S)-2-[3-(4-Hydroxymethyl-pheny1)-imidazo[1,2-
131pyridazin-6-ylamino]-3-methyl-butan-1-ol
229_0 5.263
254_0
HN
135 ))fi /
339.44
N\
(S)-243-(3-Dimethylamino-pheny1)-imidazo[1,2-
b]pyridazin-6-ylaminoF3-methyl-butan-1-ol
229_0 5.264
254_0 .0*
HN
057 Yi."1 .411-
346.43
Aar/
(S)-3-Methy1-2-(3-naphthalen-2-yl-imidazo[1,2-
b]pyridazin-6-ylamino)-butan-1-ol
229_0 5.265
254_0
HN
312
364.37
OH
F F
(S)-3-Methy1-213-(3-trifluoromethyl-pheny1)-
imidazo[1,2-b]pyridazin-6-ylanninoFbutan-1-ol
229_0 5.266
; 254_0 40.
HN
068 YI) = ?
340.38
0
(S)-2-(3-Benzo[1,3]dioxo1-5-yl-imidazo[1,2-
b]pyridazin-6-ylamino)-3-methyl-butan-1-ol
229_0 5.267
254_0 40.
HN
345
OH
316.43
(S)-3-Methy1-2-[3-(4-methyl-thiophen-2-y1)-
imidazo[1,2-b]pyridazin-6-ylaminoFbutan-1-ol

CA 02620534 2008-02-28
SRG/US/53343 - 1 1 9 - ALSTDS
229_0 5.268
254_0 /
HN
074
302.40
S
OH
(S)-3-Methy1-2-(3-thiophen-3-yl-imidazo[1,2-
b]pyridazin-6-ylarnino)-butan-1-01
229_0 5.269
254_0
FIN
168 Y."1 = ol
380.37
)4-"F
(S)-3-Methy1-213-(3-trifluoromethoxy-phenyl)-
imidazo[1,2-to]pyridazin-6-ylaminoFbutan-1-ol
229_0 5.270
254_0
HN
279
YE)H a
330.82
(S)-2-[3-(3-Chloro-phenyI)-imidazo[1,2-b]pyridazin-6-
ylamino]-3-methyl-butan-1-01
229_0 5.271
254_0
FIN
339 *".1H =
314.36
(S)-2-[3-(4-Fluoro-pheny1)-imidazo[1,2-13]pyridazin-6-
ylamino]-3-methyl-butan-1-ol
229_0 5.272
254_0 Ole
HN
204
YL1H
335.41
(S)-2-[3-(1H-Indo1-5-y1)-imidazo[1,2-b]pyridazin-6-
ylaminol-3-methyl-butan-1-ol
229_0 5.273
= 254_0 Or.
HN
347
o 339.40
NH2
3164(S)-1-Hydroxymethy1-2-methyl-propylamino)-
imidazo[1,2-bipyridazin-3-yl]-benzamide

CA 02620534 2008-02-28
SRG/US/53343 - 120 -
ALJ/TDS
229_0 5.274
254_4
HN
145
338.41
1-{3-[6-((S)-1-Hydroxymethy1-2-methyl-propylamino)-
imidazo[1,2-b]pyridazin-3-y11-phenylyethanone
229_0 5.275
254_0 Or.
HN
196327.39
Y-1
N
(S)-2-[3-(5-Methoxy-pyridin-3-y1)-imidazo[1,2-
b]pyridazin-6-ylamino]-3-methyl-butan-1-ol
229_0 5.276
153_0 40*
HN
087
--A IP
372.42
¨0
0
243-(3,4,5-Trimethoxy-pheny1)-imidazo[1,2-
b]pyridazin-6-ylamino]-butan-1-ol
229_0 5.277
153_0
ci
164
334.78
2-[3-(3-Chloro-4-fluoro-pheny1)-imidazo[1,2-
b]pyridazin-6-ylam ino]-butan-1-o1
229_0 5.278
1153_0 41*
HN
, 057
0.99 332.41/333
oti .10
2-(3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-
ylamino)-butan-1-ol
229_0 5.279
153_0
HN
168
1.02 366.34/367
110 F
213-(3-Trifluoromethoxy-pheny1)-imidazo[1,2-
b]pyridazin-6-ylamino]-butan-1-ol

CA 02620534 2008-02-28
SRG/US/53343 - 121 - ALJ/IDS
229_0 5.280
153_0
HN
074
s 0.82 288.37/289
OH
2-(3-Thiophen-3-yl-imidazo[1,2-b]pyridazin-6-
ylamino)-butan-1-ol
229_0 5.281
153_0 40.
280
-1s)
OH 1110 0.86
312.37/313
0
243-(4-Methoxy-pheny1)-imidazo[1,2-b]pyridazin-6-
ylaminoFbutan-1-ol
229_U 5.282
153_0
345
S 0.90 302.40/303
OH
243-(4-Methyl-thiophen-2-y1)-imidazo[1,2-b]pyridazin-
6-ylaminoFbutan-1-ol
229_0 5.283
153_0
FIN
279 =ci 316.79
OH
213-(3-Chloro-pheny1)-imidazo[1,2-b]pyridazin-6-
ylaminoFbutan-1-ol
' 229_0 5.284
, 153_0 1410.
311
\ N 0.79 313.36/314
OH
0
2-[3-(6-Methoxy-pyridin-3-y1)-imidazo[1,2-b]pyridazin-
6-ylaminol-butan-1-ol
229_0 5.285
153_7
FIN
468
0.67 286.34/287
oH N
213-(1 -Methyl-1 H-pyrazol-4-y1)-imidazo[1,2-
,
b]pyridazin-6-ylaminoi-butan-1-ol

CA 02620534 2008-02-28
SRG/US/53343 - 122 -
ALJ/TDS
229_0 5.286
153_0
277
`.:TI lip Br
361.24
OH
243-(3-Bromo-phenyl)-im idazo[1,2-b]pyridazin-6-
ylamino]-butan-1-ol
229_0 5.287
153_0
HN
312 F F 1.00
350.34/351
OH IP
243-(3-Trifluoromethyl-pheny1)-imidazo[1,2-
1
b]pyridazin-6-ylaminoFbutan-1-ol
229_0 5.288
153_4
140 0.86
312.37/313
OH 0\
243-(3-Methoxy-pheny1)-imidazo[1,2-b]pyridazin-6-
ylamino]-butan-1-ol
229_0 5.289
153_0
347= o 325.37
oH
3-[6-(1-Hydroxymethyl-propylamino)-imidazo[1,2-
b]pyridazin-3-y1]-benzamide
229_0 5.290
153_0
HN
140
OH *
326.35
OH
0
4-[6-(1-Hydroxymethyl-propylamino)-imidazo[1,2-
b]pyridazin-3-y1Fbenzoic acid
229_0 5.291
153_7
HN
469
OH N
362.44
410/
2-[3-(1-Benzy1-1H-pyrazol-4-y1)-imidazo[1,2-
b]pyridazin-6-ylaminoFbutan-1-ol

CA 02620534 2008-02-28
SRG/US/53343 - 123 - A
LJ/TDS
229_0 5.292
153_6
*
488
375.45
OH
N-{3-[6-(1-Hydroxymethyl-propylamino)-imidazo[1,2-
1Apyridazin-3-y1]-phenylymethanesulfonamide
229_0 5.293
153_4
H 0
145
324.38
1434641 -Hydroxymethyl-propylamino)-imidazo[1,2-
b]pyridazin-3-y1J-phenylyethanone
229_0 5.294
153_0
HN
079
OH # (3\ 342.40
0
2-[3-(3,4-Dimethoxy-pheny1)-imidazo[1,2-b]pyridazin-
6-ylaminoi-butan-1-01
229_0 5.295
153_0
HN
196
/
313.36
OH N (3\
2-[3-(5-Methoxy-pyridin-3-yI)-imidazo[1,2-b]pyridazin-
6-ylaminol-butan-1-ol
229_0 5.296
242_0 41.* =
087
411 0
384.43
---0 0
(Tetrahydro-pyran-4-y1)-(3-(3,4,5-trimethoxy-pheny1)-
imidazo[1,2-b]pyridazin-6-yI]-amine
229_0 5.297
242_4
140
II 0
324.38
[3-(3-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-y1F
(tetrahydro-pyran-4-yI)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 124 -
ALJ/TDS
229 0 5.298
242_0 "
312 F
362.35
F F
(Tetrahydro-pyran-4-y1)43-(3-trifluoromethyl-phenyl)-
imidazo[1,2-1Apyridazin-6-y1Famine
229_0 5.299
' 242_0
285
324.38
HO
{446-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-
1Apyridazin-3-y11-phenylymethanol
229_0 5.300
242_0 4.*
345 /S
314.41
[3-(4-Methyl-thiophen-2-y1)-imidazo[1,2-b]pyridazin-6-
y1]-(tetrahydro-pyran-4-y1)-amine
229_0 5.301
242_0
164
11
346.79
[3-(3-Chloro-4-fluoro-phenyI)-imidazo[1,2-b]pyridazin-
i 6-y1]-(tetrahydro-pyran-4-y1)-amine
229_0 5.302
1242_0 aN ere =
; 277
373.25
Br
[3-(3-Bromo-pheny1)-imidazo[1,2-131pyridazin-6-y1]-
(tetrahydro-pyran-4-yI)-amine
229_0 5.303
242_7
468
298.35
--N
N
[3-(1-Methy1-1H-pyrazol-4-y1)-imidazo[1,2-b]pyridazin-
. 6-y1]-(tetrahydro-pyran-4-y1)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 125 - ALJ/TDS
229_0 5.304
242_0
291
411
324.38
OH
{3-[6-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-
b]pyridazin-3-y1]-phenylymethanol
229_0 5.305
242_0
196 /
325.37
N
[3-(5-Methoxy-pyridin-3-y1)-imidazo[1,2-b]pyridazin-6-
y1]-(tetrahydro-pyran-4-y1)-amine
229_0 5.306
242_0 N or.
280
411
324.38
0
[3-(4-Methoxy-pheny1)-imidazo[1,2-b]pyridazin-6-y11-
(tetrahydro-pyran-4-yI)-amine
229_0 5.307
242_0
339
312.35
[3-(4-Fluoro-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-
(tetrahydro-pyran-4-yI)-amine
1229_0 5.308
242_0 api
=
204
333.39
[3-(1H-Indo1-5-y1)-imidazo[1,2-b]pyridazin-6-yI]-
' (tetrahydro-pyran-4-yI)-amine
229_0 5.309
242_0 N
1135 =
337.43
N/
1 [3-(3-Dimethylamino-pheny1)-imidazo[1,2-1Apyridazin-
6-y11-(tetrahydro-pyran-4-y1)-amine
_ _

CA 02620534 2008-02-28
SRG/US/53343 - 126 -
ALJ/TDS
229_0 5.310
242_0
057
1.01 344.42/345
= (3-Naphthalen-2-yl-imidazo[1,2-b]pyridazin-6-y1)-
(tetrahydro-pyran-4-y1)-amine
229_0 5.311
242_0 N
167
0.95 322.41/323
[3-(3,4-Dimethyl-phenyl)-imidazo[1,2-1Apyridazin-6-y1]-
(tetrahydro-pyran-4-y1)-amine
229_0 5.312
242_0 N N /
142 / 0.81
284.32/285
(3-Furan-2-yl-imidazo[1,2-1Apyridazin-6-y1)-
(tetrahydro-pyran-4-yI)-amine
229_0 5.313
242_0 N
192 AI 0
0.67 381.43/382
11-A
H
N-(2-Hydroxy-ethyl)-316-(tetrahydro-pyran-4-
ylamino)-imidazo[1,2-1Apyridazin-3-ylybenzamide
229_0 5.314
1242_2 =
! 175
0.90
352.39/353
0 \
416-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-
blpyridazin-3-y1]-benzoic acid methyl ester
229_0 5.315
242_4 /
139
0.90 308.38/309
(Tetrahydro-pyran-4-y1)-(3-p-tolyl-imidazo[1,2-
b]pyridazin-6-y1)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 127 -
ALJ/TDS
229_0 5.316 eft
242_0
333
0.68 309.37/310
NH,
[3-(4-Amino-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-
(tetrahydro-pyran-4-y1)-amine
229_0 5.317
242_0
004
337.43
N--_
[3-(4-Dimethylamino-pheny1)-imidazo[1,2-b]pyridazin-
6-y11-(tetrahydro-pyran-4-y1)-amine
229_0 5.318
242_0 4s1
081 t 0.73
351.41/352
/7 ¨0
N-{316-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-
b]pyridazin-3-y1]-phenylyacetamide
229_0 5.319
242_0
005
309.37
NH2
[3-(3-Amino-pheny1)-imidazo[1,2-1Apyridazin-6-y1]-
(tetrahydro-pyran-4-yI)-amine
229_0 5.320
1242_4 erik.
038
411 0.85 312.35/313
[3-(2-Fluoro-pheny1)-imidazo[1,2-1Apyridazin-6-y1]-
(tetrahydro-pyran-4-yI)-amine
229_0 5.321
242_0
062
344.42
(3-Naphthalen-1-yl-imidazo[1,2-1Apyridazin-6-y1)-
L_. (tetrahydro-pyran-4-yI)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 128 - A
Ulf-DS
229_0 5.322
242_0 -. 24 /
071 \N 0.65
295.34/296
(3-Pyridin-3-yl-imidazo[1,2-b]pyridazin-6-y1)-
(tetrahydro-pyran-4-y1)-amine
229_0 5.323
242_0
160
328.80
CI
[3-(4-Chloro-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-
(tetrahydro-pyran-4-y1)-amine
229_0 5.324
242_0
068
, 338.37
(3-Benzo[1,3]dioxo1-5-yl-imidazo[1,2-b]pyridazin-6-y1)-
(tetrahydro-pyran-4-y1)-annine
229_0 5.325
242_0 oa 40e
284 # 0.74
310.36/311 OH
346-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-
b]pyridazin-3-yI]-phenol
229_0 5.326
1242_0 aN
074 0.84
300.38/301
\ s
(Tetrahydro-pyran-4-yI)-(3-thiophen-3-yl-imidazo[1,2-
b]pyridazin-6-yI)-amine
229_0 5.327
242_0 a
079 0/ 0.81
354.41/355
0
[3-(3,4-Dimethoxy-phenyI)-imidazo[1,2-b]pyridazin-6-
yI]-(tetrahydro-pyran-4-y1)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 129 -
ALJ/TDS
229_0 5.328
242_0
168
41 0 1.06
378.35/379
FF
(Tetrahydro-pyran-4-y1)13-(3-trifluoromethoxy-
pheny1)-imidazo[1,2-b]pyridazin-6-yli-amine
229_0 5.329
242_0
313
F 312.35
[3-(3-Fluoro-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-
,
(tetrahydro-pyran-4-yI)-amine
229_0 5.330
242_0
314
* 0 340.38
OH
2-Methoxy-4-[6-(tetrahydro-pyran-4-ylamino)-
imidazo[1,2-1Apyridazin-3-y1Fphenol
229_0 5.331
242_4
147 0.83 300.38/301
(Tetrahydro-pyran-4-yI)-(3-thiophen-2-yl-im idazo[1, 2-
b]pyridazin-6-yI)-am ine
229_0 5.332
242_7 41*
I 467 0.59
284.32/285
=
[3-(1H-Pyrazol-4-y1)-imidazo[1,2-1Apyridazin-6-A-
(tetrahydro-pyran-4-yI)-amine
229_0 5.333
242_0 aN 40*
347 At 0
337.38
NH,
3-[6-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-
,
b]pyridazin-3-y1]-benzamide

CA 02620534 2008-02-28
SRG/US/53343 - 130 -
ALJ/TDS
229_0 5.334
242_7 rs,C3
469
374.45
[3-(1-Benzy1-1H-pyrazol-4-y1)-imidazo[1,2-1Apyridazin-
6-y1]-(tetrahydro-pyran-4-y1)-amine
229_0 5.335
242_0
140
410
338.37
0
HO
446-(Tetrahydro-pyran-4-ylarnino)-imidazo[1,2-
b]pyridazin-3-y1]-benzoic acid
229_0 5.336
242_6
488 = "I
387.46
01-
0
N-{3-[6-(Tetrahydro-pyran-4-ylamino)-imidazo[1,2-
1Apyridazin-3-y1]-pheny1}-methanesulfonamide
229_0 5.337
242_0 N
1279 328.80
[3-(3-Chloro-pheny1)-imidazo[1,2-b]pyridazin-6-y1]-
. (tetrahydro-pyran-4-y1)-amine
1229_0 5.338 HO..
1240 0
-
354.41/353
314
0 0.70
(negative
mode)
OH
4-[6-(4-Hydroxy-cyclohexylamino)-imidazo[1,2-
b]pyridazin-3-y1]-2-methoxy-phenol

CA 02620534 2008-02-28
SRG/US/53343 - 131 -
ALJ/IDS
229_0 5.339 HO a l
240_0 /
168
392.38
f
443-(3-Trifluoromethoxy-phenyl)-innidazo[1, 2-
b]pyridazin-6-ylamino]-cyclohexanol
229_0 5.340 HOTa
240_4
140
it 0 0.79 338.41/339
413-(3-Methoxy-pheny1)-imidazo[1,2-b]pyridazin-6-
ylaminol-cyclohexanol
229_0 5.341 HOla
240_0 /
074
314.41
\ s
4-(3-Thiophen-3-yl-imidazo[1,2-b]pyridazin-6-
ylamino)-cyclohexanol
229_0 5.342 HOlia
240_0
076 / s
364.47
4-(3-Benzo[b]thiophen-2-yl-imidazo[1,2-b]pyridazin-6-
ylaminoycyclohexanol
229_0 5.343 HO
I 240_0 40.
1135 * tl/
351.45
4-[3-(3-Dimethylamino-pheny1)-imidazo[1,2-
b]pyridazin-6-ylaminol-cyclohexanol
229_0 5.344 HO ,
240_0 /
313
F
326.37
413-(3-Fluoro-pheny1)-imidazo[1,2-b]pyridazin-6-
ylamino]-cyclohexanol

CA 02620534 2008-02-28
SRG/US/53343 - 132 - ALJ/TDS
229_0 5.345 HO
240_0 140*
062 0.83 358.44/359
4-(3-Naphthalen-1-yl-imidazo[1,2-b]pyridazin-6-
ylamino)-cyclohexanol
229_0 5.346 HO
240_0 40.
081
= rslc,_
365.44
0
N-{316-(4-Hydroxy-cyclohexylam ino)-im idazo[1, 2-
b]pyridazin-3-A-phenylyacetamide
229_0 5.347 HOõ.ra
240_0
080
324.38
OH
4-[6-(4-Hydroxy-cyclohexylamino)-imidazo[1,2-
1Apyridazin-3-yll-phenol
229_0 5.348 HOla
240_0 /
057
358.44
4-(3-Naphthalen-2-yl-imidazo[1,2-1Apyridazin-6-
ylaminoycyclohexanol
229_0 5.349 HOia
240_0
=
i 061
308.38
4-(3-Phenyl-imidazo[1,2-13]pyridazin-6-ylamino)-
cyclohexanol
229_0 5.350 HOla
240_0
204
347.42
\ NH
4-[3-(1H-Indo1-5-y1)-imidazo[1,2-b]pyridazin-6-
_ylaminol-cyclohexanol

CA 02620534 2008-02-28
SRG/US/53343 - 133 -
ALSTDS
229_0 5.351 HOI:a
240_0 /
004
351.45
4-[3-(4-Dimethylamino-pheny1)-imidazo[1,2-
b]pyridazin-6-ylaminoRyclohexanol
229_0 5.352 HO-.
240_0 /
280
338.41
413-(4-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-
ylaminol-cyclohexanol
229_0 5.353 H00,
240_0 Nlk
078 359.43
4-(3-Quinolin-8-yl-imidazo[1,2-b]pyridazin-6-ylamino)-
cyclohexanol
229_0 5.354
240_0
142 = / 0
298.34
4-(3-Furan-2-yl-imidazo[1,2-19]pyridazin-6-ylamino)-
cyclohexanol
' 229_0 5.355 HO
1240_2
175
366.42/365
0.82
(negative
mode)
0 (:\
446-(4-Hydroxy-cyclohexylamino)-imidazo[1,2-
b]pyridazin-3-yll-benzoic acid methyl ester
229_0 5.356 H01,
240_0 3 /
085
392.38
FfF
4-[3-(4-Trifluoromethoxy-phenyI)-imidazo[1,2-
b]pyridazin-6-ylamino]-cyclohexanol

CA 02620534 2008-02-28
SRG/US/53343 - 134-
ALJTIDS
229_0 5.357
240_0
167
336.44
443-(3,4-Dimethyl-pheny1)-imidazo[1,2-1D]pyridazin-6-
ylannino]-cyclohexanol
229_0 5.358 HOra
240_0
285
411
338.41
HO
1 443-(4-Hydroxymethyl-pheny1)-imidazo[1,2-
1Apyridazin-6-ylaminol-cyclohexanol
229_0 5.359 HOla
240_0
160
342.83
443-(4-Chloro-pheny1)-imidazo[1,2-b]pyridazin-6-
ylaminol-cyclohexanol
229_0 5.360
240_0
311 /
339.40
443-(6-Methoxy-pyridin-3-y1)-imidazo[1,2-b]pyridazin-
i 6-ylamino]cyclohexanol
' 229 0 5.361 H00,
I ¨
240_0
, 196
/
339.40
443-(5-Methoxy-pyridin-3-y1)-imidazo[1,2-1Apyridazin-
6-ylaminol-cyclohexanol
229_0 5.362 HO
240_0
284 it
324.38 OH
3-[6-(4-Hydroxy-cyclohexylamino)-imidazo[1,2-
,
Npyridazin-3-yl1-phenol

CA 02620534 2008-02-28
SRG/US/53343 - 135 -
ALJ/TDS
229_0 5.363 HOla
240_0
140
352.39
OH
0
4-[6-(4-Hydroxy-cyclohexylamino)-imidazo[1,2-
b]pyridazin-3-y11-benzoic acid
229_4 5.364
051_0
087
it 0 354.41
¨0 0
Cyclopropylmethy143-(3,4,5-trimethoxy-pheny1)-
imidazo[1,2-13]pyridazin-6-yll-amine
229_4 5.365
051_0 \7/N
314
o 310.36
OH
446-(Cyclopropylmethyl-amino)-imidazo[1,2-
b]pyridazin-3-y11-2-methoxy-phenol
229_4 5.366
051_0
V)\-1
079
o 324.38
0¨
,
Cyclopropylmethyl-[3-(3,4-dimethoxy-phenyI)-
imidazo[1,2-Npyridazin-6-y0-amine
229_4 5.367
051_0 V1-1
135 is( 307.40
Cyclopropylmethy143-(3-dimethylamino-pheny1)-
imidazo[1,2-b]pyridazin-6-y1Famine
229_4 5.368
, 051_0
\71N-1
069 /
265.32
Cyclopropylmethyl-(3-pyridin-4-yl-irnidazo[1,2-
blpyridazin-6-y1)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 136 -
ALJ/TDS
229_4 5.369
051_0 N /
291
294.36
OH
{346-(Cyclopropylmethyl-amino)-imidazo[1,2-
b]pyridazin-3-y1J-pheny1}-methanol
229_4 5.370
051_4 sN
40*
140
* 0
294.36
Cyclopropylmethy113-(3-methoxy-pheny1)-
imidazo[1,2-1Apyridazin-6-y11-amine
229_4 5.371
051_7
468
268.32
N N
Cyclopropylmethyl-[3-(1-methy1-1H-pyrazol-4-y1)-
imidazo[1,2-b]pyridazin-6-01-amine
229_4 5.372
051_7
NH
467
254.30
Cyclopropylmethyl-[3-(1H-pyrazol-4-y1)-imidazo[1,2-
b]pyridazin-6-y1Famine
229_4 5.373
051_0
068
308.34
0
(3-Benzo[1,3]clioxol-5-yl-imidazo[1,2-b]pyridazin-6-y1)-
cyclopropylmethyl-amine
229_4 5.374
051_0
280
294.36
0
Cyclopropylmethy143-(4-methoxy-pheny1)-
imidazo[1,2-b]pyridazin-6-y1]-amine

CA 02620534 2008-02-28
SRG/US/53343 - 137 - ALJ/TDS
229_4 5.375
051_0 \Kts,
074
270.36
\ s
Cyclopropylmethyl-(3-thiophen-3-yl-imidazo[1,2-
b]pyridazin-6-y1)-amine
229_4 5.376
051_0
311 /
295.34
0
Cyclopropylmethyl-[3-(6-methoxy-pyridin-3-yI)-
imidazo[1,2-b]pyridazin-6-y1Famine
229_4 5.377
051_0 4s1
345
284.39
Cyclopropylmethyl-[3-(4-methyl-thiophen-2-yI)-
imidazo[1,2-b]pyridazin-6-y1Famine
229_4 5.378
051_0 40.
\Y-N
081 = 1"1\__
321.38
O
N-{346-(Cyclopropylmethyl-amino)-imidazo[1,2-
1Apyridazin-3-ylj-phenylyacetamide
229_4 5.379
051_0 vN
192 0
351.41
HN-Th
OH
316-(Cyclopropylmethyl-amino)-imidazo[1,2-
1Apyridazin-3-A-N-(2-hydroxy-ethyl)-benzamide
229_4 5.380
051_0 40.
285
294.36
HO
(4-[6-(Cyclopropylmethy4-amino)-im idazo[1,2-
b]pyridazin-3-yli-phenylymethanol

CA 02620534 2008-02-28
SRG/US/53343 - 138 -
ALJ/TDS
229_4 5.381
051_0
080
280.33
OH
446-(Cyclopropylmethyl-amino)-imidazo[1,2-
b]pyridazin-3-01-phenol
229_4 5.382
051_0
.V)1
284
280.33
OH
3-[6-(Cyclopropylmethyl-amino)-imidazo[1,2-
1D]pyridazin-311]-phenol
229_4 5.383
051_6
488 =
357.44
o-
0
N-{346-(Cyclopropylmethyl-amino)-imidazo[1,2-
b]pyridazin-3-y11-pheny1}-methanesulfonamide
229_4 5.384
051_0
'711
139 0
308.34
OH
3-[6-(Cyclopropylmethyl-amino)-imidazo[1,2-
1Apyridazin-3-yli-benzoic acid
229_4 5.385
; 051_7 00*
= V711
469
,N
1
344.42
4111
[3-(1-Benzy1-1H-pyrazol-4-y1)-imidazo[1,2-b]pyridazin-
6-A-cyclopropylmethyl-amine
229_4 5.386
051_U
140
308.34
0
HO
446-(Cyclopropylmethyl-amino)-imidazo[1,2-
b]pyridazin-3-y11-benzoic acid

CA 02620534 2008-02-28
SRG/US/53343 - 139 -
ALJ/TDS
229_4 5.387
051_0 01*
\7.
347 11 o
307.36
NH,
3-[6-(Cyclopropylmethyl-amino)-imidazo[1,2-
b]pyridazin-3-y11-benzamide
229_4 5.388
051_4
145 0
306.37
1-{346-(Cyclopropylmethyl-amino)-imidazo[1,2-
b]pyridazin-3-y1]-pheny1}-ethanone
, 229_4 5.389
051_4 \7."
1147
270.36
Cyclopropylmethyl-(3-thiophen-2-yl-imidazo[1,2-
b]pyridazin-6-y1)-amine
Description of the HPLC-MS analysis conditions for the examples listed in
Table 5:
Detection: UV = 200 ¨ 350 nm (Waters Acquity HPLC)/ MS 100-800 Daltons; 20 V
(Micromass / Waters ZQ 4000); column: X Bridge (Waters), 2.1 x 50 mm, BEH
1.7 pm; eluent: A: H20/0.05% HCOOH, B: CH3CN/0.05% HCOOH.
Gradient: 10-90% B in 1.7 min, 90% B for 0.2 min, 98-2% B in 0.6 min; flow
rate:
1.3 ml/min.
P-(2-Methoxypyridin-4-y0imidazo[1,2-13.1pyridazin-6-Apiperidin-4-ylamine
(Example 6.0)
FiNa
N

CA 02620534 2008-02-28
SRG/US/53343 - 140 -
ALJ/TDS
Stage A: 443-(2-methoxypyridin-4-yl)imidazo[1,2-Npyridazin-6-
ylamino]piperidine-1-carboxylic acid tert-butyl ester (Example 6.1)
.4,0ANo,
CI
292 mg of 443-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-6-
ylamino]piperidine-
1-carboxylic acid tert-butyl ester were prepared from 300 mg (1.15 mmol) of 6-
chloro-3-(2-methoxypyridin-4-y0imidazo[1,2-b]pyridazine (Example 1.14) and
230 mg (1.15 mmol) of 4-aminopiperidine-1-carboxylic acid tert-butyl ester
(CAS
No. 87120-72-7) by method A.
1H-NMR (300 MHz, d6-DMS0): 8 = 1.32 ¨ 1.38 (m, 11H); 2.02 ¨ 2.08 (m, 2H);
2.92 ¨ 3.00 (m, 2H); 3.72 ¨ 3.92 (m, 6H); 6.73 (d, 1H); 7.17 ¨ 7.19 (m, 1H);
7.64 ¨
7.66 (m, 1H); 7.76 ¨7.79 (m, 2H); 8.11 ¨8.16 (m, 2H) ppm.
MS (ES+): m/z = 425 (M+H)+ [mol. weight = 424.51].
Stage 13: (3-(2-methoxypyridin-4-y0imidazo[1,2-13.1pyridazin-6-yllpiperidin-4-
ylamine (Example 6.0)
0
0)LN HNia
280 mg (0.66 mmol) of 443-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-6-
ylamino]piperidine-1-carboxylic acid tert-butyl ester were introduced into 3
ml of THF

CA 02620534 2008-02-28
SRG/US/53343 - 141 -
ALJ/TDS
and, after addition of 0.8 ml of HCI in dioxane (4M), stirred at RT overnight.
HCI
(conc.) was added, and the mixture was heated at 70 C for 4 hours. The
reaction
was diluted with water, adjusted to pH 11 with Et3N and extracted three times
with
ethyl acetate. The combined organic phases were filtered through a silicone
filter
(from Whatman) and concentrated. In the final fractionation by chromatography
on
silica gel, 92 mg of the desired product were isolated.
1H-NMR (300 MHz, d6-DMS0): 6 = 1.30 - 1.43 (m, 2H); 2.03 - 2.08 (m, 2H); 2.59 -

2.67 (m, 2H); 2.99 - 3.06 (m, 2H); 3.66 - 3.75 (m, 1H), 3.89 (s, 3H); 6.77 (d,
1H);
7.15 - 7.18 (m, 1H); 7.66 - 7.69 (m, 1H); 7.80 (d, 1H); 8.87 (s, 1H); 8.15 -
8.19 (m,
2H) ppm.
MS (ES+): m/z = 325 (M+H)+ [mol. weight = 324.39].
The following example was prepared analogously:
Example Structure and name of the main
isomer 11-1-NMR Mol. weight/
No. MS (ES+)
[M+1]+
6.2 HN (300 MHz, d6-DMS0): 324.39/325
Cr/ 8 = 1.22 - 1.35 (m,
2H); 1.92 - 1.97 (m,
/ \ 2H); 2.49 - 2.57 (m,
=
2H, partly covered by
solvent); 2.90 - 2.97
(m, 2H); 3.55 - 3.67
(m, 1H); 3.86 (s, 3H);
[3-(6-Methoxy-pyridin-3-y1)-imidazo[1,2-
6.64 (d, 1H); 6.96 -
b]pyridazin-6-yli-piperidin-4-yl-amine
6.98 (m, 1H); 7.70 (d,
1H); 7.80 (s, 1H); 8.38
(dd, 1H) ppm.

CA 02620534 2008-02-28
SRG/US/53343 - 142 -
ALJ/TDS
346-(2-Hydroxyethylamino)imidazo[1,2-b]pyridazin-3-yllbenzenesulfonamide
(Example 7.0)
FION
it )7
S.-NH
H it
2
0
82 mg (0.21 mmol) of N-tert-butyl-346-(2-hydroxyethylamino)imidazo[1,2-
b]pyridazin-3-yl]benzenesulfonamide were mixed under argon with 1.7 ml of
trifluoroacetic acid and stirred at 50 C for 5 hours. After cooling, the
mixture was
concentrated in vacuo, and the residue was taken up in ethyl acetate. The
organic
phase was washed with saturated NaHCO3 solution and saturated NaCI solution,
filtered through a Whatman filter and concentrated. The resulting residue was
purified by chromatography (DCM/Et0H 6:4). 47 mg of the product were obtained.
1H-NMR (400 MHz, d6-DMS0): 6 = 3.36 ¨ 3.40 (m, 2H); 3.61 ¨ 3.65 (m, 2H); 4.77
(t,
1H); 6.78 (d, 1H); 7.17 (t, 1H); 7.35 (s, 2H); 7.59 ¨ 7.63 (m, 1H); 7.70 -
7.76 (m, 2H);
7.95 (s, 1H); 8.25 (d, 1H); 8.87 (m, 1H) ppm.
The following example was prepared analogously:
Example Structure and name of the main
isomer 'H-NMR Mol. weight!
No. MS
(ESI)
[M+1]+

CA 02620534 2008-02-28
SRG/US/53343 - 143 -
ALJ/TDS
MW:
HN N 333.37
=
OH 334
7.1Se
H2Ni '0
416-(2-Hydroxy-ethylamino)-innidazo
[1,2-1Apyridazin-3-y11-benzenesulfon
amide
The following examples were prepared from 4-(6-chloroimidazo[1,2-1Apyridazin-3-
yl)phenol and the appropriate amine in analogy to Example 1.5:
Example Structure and name of the main isomer
11-I-NMR Mol. weight /
No. MS (ES+)
MW 311.39
HN N
,f4 MS (ES+):
[M+11+ 312
8.0 NY
OH
446-(3-Dimethylamino-propylamino)-
imidazo[1,2-b]pyridazin-3-y1]-phenol

CA 02620534 2008-02-28
SRG/US/53343 - 144 -
ALJ/TDS
(DMSO-d6, stored
over molecular
HN N
sieves): 8 = 2.40 (m,
4H); 2.54 (m, 2H);
8.1 3.37 (m, 2H); 3.56 (m,
OH 4H); 6.63 (d, 1H); 6.80
0 (d, 1H); 6.92 (m, 1H);
446-(2-Morpholin-4-yl-ethylam ino)-
7.66 (m, 2H); 7.94 (d,
1H) ppm .
imidazo[1,2-b]pyridazin-3-y11-phenol
Biological effects
The following examples describe the biological effect of the compounds of the
invention:
It is clear to the skilled worker that there is a number of disorders in which
the
cause of the disorder derives from a dysfunction of one or more kinases.
Dysfunctions of kinases can be induced by a large number of mechanisms, e.g. a
kinase may be overexpressed, leading to a faulty cellular activity, or a
mutated
kinase may be overexpressed, likewise leading to a faulty cellular activity.
The
faulty cellular activity may be for example a faulty cellular proliferation,
especially
an increased cellular proliferation (cellular hyperproliferation). The result
of such
dysfunctions may be for example a disorder which is characterized by
overexpression or mutation of the kinase.
Appropriate assays for testing the efficacy of the compounds of the invention
for
the ability to modulate kinase activity are known. Also known are assays in
order to
investigate the efficacy of the compounds of the invention in modulating
cellular
proliferation.

CA 02620534 2008-02-28
SRG/US/53343 - 145 -
ALJ/TDS
The following biological examples therefore serve merely to describe by way of
example the uses according to the invention of the claimed compounds and are
therefore not to be understood as limiting in any way.
Significance of IL-2 in the T cell immune response
The extent to which test substance influence antibody-induced interleukin 2
(IL-2)
secretion was investigated in the following test system. IL-2 represents a
central
cytokine which is produced and released by activated T cells. IL-2 synthesis
in the
T cells is regulated by a plurality of kinases. An inhibitory effect of
substances on
kinases leads inter alia to inhibition of IL-2 synthesis and inhibition of the
T cell
io immune response. The cytokine determinations were carried out using an
ELISA
kit.
Description of the test system
Peripheral blood mononuclear cells (PBMC) were isolated from heparinized human
is whole blood by gradient centrifugation using Histopaque 1077 (Sigma) at
room
temperature, and the erythrocytes were lyzed hypotonically and, after washing
twice in PBS, taken up in cell culture medium (10% fetal inactivated calf
serum in
RPMI-1640 + Glutamax-I [Gibco]).
The 96 well culture plates (Costar) were previously incubated with 100 pl of
20 antibody solution in PBS 0.1 pg/ml in PBS [Gibco]) per well at 4 C for
18 hours.
The antibodies used were anti-CD3 and anti-CD28 monoclonal antibodies
(PharMingen). After washing with PBS three times, the plates were charged with
200 pl of the cell suspension (40 000 cells/well). In addition, the test
substances
were added in concentrations such that they were present in concentrations of
25 1 X 106_ 1X10-12 M.

CA 02620534 2008-02-28
SRG/US/53343 - 146 -
ALJ/TDS
The cultures were incubated in an incubator at 37 C for 20 hours. After this
incubation, the plates were briefly shaken and centrifuged, and 250 pl of
supernatant were removed, and the supernatants were then frozen at -20 C.
Interleukin-2 was determined using an ELISA kit (Bioscience), and the
absorption
of the color change was analyzed in a SpectraMax 340 PC (wavelength 450 nm).
Active substances brought about a reduction in the absorption.
Table 1: Assay data
Example Structure Inhibition IC50 [mo1/1]
(concentration
No. of PKC for 50% inhibition of IL-2)
theta inhibition at 10 pM
IC50
[mo1/1]
OP 3070 6.1 x 10-6 1.4x10-6, >95%
inhibition
N N at 10 pM
(3-Phenyl-imidazo[1,2-b]pyridazin-6
-y1)-(3-pyrrolidin-1-yl-propy1)-amine
OP 3071 1.7 x 10-5 2.5x106, >95% inhibition
,4 /
N N at 10 pM
(3-Morpholin-4-yl-propyI)-(3-phenyl-
imidazo[1,2-b]pyridazin-6-yI)-amine
OP 3073 2.5 x 10-7 2.1x10-7, >95%
inhibition
N at 10 pM
11' CI
[3-(3-Chloro-phenyI)-imidazo[1,2-b]
pyridazin-6-yI]-(3-pyrrolidin-1-yl-
propyI)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 147 -
ALJ/TDS
OP 3074
4.1 x10-' 9.2x10-7, >95% inhibition
at 10 pM
CI
[3-(3-Chloro-pheny1)-imidazo[1,2-13]
pyridazin-6-y1]-(3-morpholin-4-yl-
propyI)-amine
KE1322-
1.29 x 10-5 1.7 x 10-6
002-a
Nj
(3-Imidazol-1-yl-propy1)-(3-phenyl-
imidazo[1,2-b]pyridazin-6-yI)-amine
KE1322-
fµl 1.13 x 10-5 2.0 x 10-6
006-a
/k.
N.N
=
[345-Methy1-1H-pyrazol-4-y1)-propyl]
(3-phenyl-imidazo[1,2-b]pyridazin-6-:
-amine
KEI322-5.4 x 10-6 1.1 x 10-6
010-a NI
N N
N*1*,N*1*-Diethyl-N*4*-(3-phenyl-
imidazo[1,2-b]pyridazin-6-y1)-pentane
-1,4-diamine
KE1322- 5.5 x 10-6 2.6 x 10-6
011-a
N
110
N,N-Diethyl-N'-(3-phenyl-imidazo
[1,2-13]pyridazin-6-y1)-propane-1,3-
diamine

CA 02620534 2008-02-28
SRG/US/53343 - 148 -
ALJ/TDS
KE1322- 7.2 x 10-6 1.1 x 10-6
014-a .."(-=/
NNj "
* CI
[3-(3-Chloro-pheny1)-imidazo[1,2-13]
pyridazin-6-yI]-(3-imidazol-1-yl-
propyI)-amine
KE1322-
2.2 x 10-7 2.9 x 10-7
022-a ==N
N N
# CI
N*4*-[3-(3-Chloro-phenyI)-imidazo
[1,2-b]pyridazin-6-y1J-N*1*,N*1*-
diethyl-pentane-1,4-diamine
KE1322- 2.5 x 10-7 2.1 x 10-7
023-a A- -1;1 /
N N N
* CI
N'-[3-(3-Chloro-phenyl)-imidazo
[1,2-b]pyridazin-6-y1FN,N-diethyl-
propane-1,3-diamine
KE1322- 1.7 x 10-6 1.0 x 10-6
024-a ON
N
* CI
[3-(3-Chloro-phenyl)-imidazo
[1,2-13]pyridazin-6-yI]-(2-pyrrolidin-
1-yl-ethyl)-amine

CA 02620534 2008-02-28
SRG/US/53343 - 149 -
ALJ/TDS
KEI322- 7.0 x 10-6
028-a
(r1
/ I
N-N
Cyclohexylmethy143-(I-methyl-1H-
pyrazol-4-y1)-imidazo[1,2-13]pyridazin
6-y1Famine
KE1322- N 7.2 x 10-6 0.7 x 10-6
030-a
N-N
[341-Methy1-1H-pyrazol-4-y1)-imidazc
[1,2-b]pyridazin-6-y1H3-(5-methyl-
1H-pyrazol-4-y1)-propylFamine
KE1322-
1.3 x 10-5 0.4 x 10-6
042-a
NN /
S
[3-(5-Methyl-1 H-pyrazol-4-y1)-
propy1]-(3-thiophen-3-yl-imidazo-
[1,2-13]pyridazin-6-y1)-amine
ALK1 Kinase flashplate assay
In order to examine the activity of compounds, an ALK1 kinase flashplate assay
was established and used.
ALK1 phosphorylates serine/threonine residues of the biotinylated substrate
bovine
a-casein in the presence of [7-3313]ATP. The radiolabeled product is detected
through binding to streptavidin-coated flashplates. The biotin residues of the
biotinylated casein bind with high affinity to the streptavidin. Radiolabeled

CA 02620534 2008-02-28
SRG/US/53343 - 150 -
ALJ/TDS
biotinylated casein resulting from the ALK1 kinase reaction causes a
chemiluminescence signal after the streptavidin-mediated binding to the
scintillator-
containing surface of the flashplate has taken place. This signal derives from
the
closeness of the radioactive label to the scintillator in the surface of the
well of the
flashplate. Unphosphorylated substrate causes no signal because it contains no
radiolabeled phosphate groups. Free [y-33P]ATP remaining unbound in the
solution
(supernatant) is washed out of the wells of the flashplates and therefore
makes no
significant contribution to a background signal. The measured signals are
therefore
a measure of the ALK1 kinase activity. Measurement takes place in a Perkin-
Elmer
io top count apparatus or a Perkin-Elmer ViewLux instrument.
Material:
Enzyme: purified human recombinant ALK1 kinase (GST fused to the intracellular
domain of ALK1 [His142-G1n503]); self-prepared; aliquots are stored at -80 C;
diluted enzyme working solution: 2.5 ng/pl ALK1 (in assay buffer) is freshly
prepared and stored on ice until used.
Substrate: biotinylated bovine a-casein. Unbiotinylated casein from Sigma is
biotinylated by standard methods using a biotin-N-hydroxysuccinimide (NHS)
ester.
Substrate working solution: 0.83 pM ATP, 1.67 pM biotinylated a-casein, 7.4
nCi of
[11-3313]ATP/p1 in assay buffer
Assay plates: 384-well plates, small volume, white, Greiner (# 784075)
Flashplates: streptavidin-coated flashplates, Perkin Elmer (384-Well #
SPM410A)
Assay buffer: 50 mM Tris/HCI pH 8.0, 1 mM MnCl2, 1 mM DTT, 0.01% NP40, 0.5x
complete EDTA-free
Stop solution: 33.3 pM ATP, 33.3 mM EDTA, 0.07% Triton X-100 in PBS
Saturation solution for flashplates: 100 pM ATP, 0.2% Triton X-100 in PBS
Adhesive film for plates: Greiner (# 676080)
Description of assay

CA 02620534 2008-02-28
SRG/US/53343 - 151 -
ALJ/TDS
Protocol for a 5 pl assay (all steps are carried out at 20 C; a CyBi-well
pipettor and
a multidrop microdispensor is used for pipetting):
1. 50 nl or 250 nl of substance in 100% DMSO
2. addition of 3 pl of substrate working solution using a CyBi-Well pipettor
3. addition of 2 pl of enzyme working solution using a multidrop
microdispensor
Incubation at room temperature (20 C) for 60 min
4. addition of 15 pi of stop solution using a CyBi-Well pipettor
5. transfer of 18 pl of assay mixture into flashplates** using a CyBi-Well
pipettor
Incubation at room temperature for at least 3 h or at 4 C overnight in order
to allow
lo binding to the streptavidin-coated flashplates.
6. washing of the flashplates three times with 50 pl of PBS without Ca ++ and
Mg++
each time
7. sealing of the plates with adhesive film
8. measurement in the top count (60 sec/well)
**Saturation of the flashplates: the flashplates are preincubated with 50 pl
of
saturation solution for at least 1 h. 18 pl of this solution are discarded
before 18 pl
of assay mixture are transferred into the flashplates
Final concentrations calculated for a reaction volume of 5 pl: 5 ng of
ALK1/well;
1 pM biotinylated a-casein; 0.5 pM ATP; 22 nCi/well [y-331:1ATP; 1 mM MnC12,
1 mM DTT; 50 mM Tris-HCI, pH 8.0; 0.01% NP40; 0.5x complete EDTA-free; 1 (Yo
=
or 5% DMSO.
The data are normalized (enzyme reaction without inhibitor = 0% inhibition,
enzyme reaction in the presence of 10 mM EDTA = 100% inhibition) and 1050
values are calculated using a 4-parameter fit with the aid of an in-house
software.
ALK4 kinase flashplate assay
In order to examine the activity of compounds, an ALK4 kinase flashplate assay
was established and used.

CA 02620534 2008-02-28
SRG/US/53343 - 152-
ALJ/TDS
ALK4 phosphorylates serine/threonine residues of the biotinylated substrate
bovine
a-casein in the presence of [y-33P]ATP. The radiolabeled product is detected
through binding to streptavidin-coated flashplates. The biotin residues of the
biotinylated casein bind with high affinity to the streptavidin. Radiolabeled
biotinylated casein resulting from the ALK4 kinase reaction causes a
chemiluminescence signal after the streptavid in-mediated binding to the
scintillator-
containing surface of the flashplate has taken place. This signal derives from
the
closeness of the radioactive label to the scintillator in the surface of the
well of the
flashplate. Unphosphorylated substrate causes no signal because it contains no
radiolabeled phosphate groups. Free [y-33P]ATP remaining unbound in the
solution
(supernatant) is washed out of the wells of the flashplates and therefore
makes no
significant contribution to a background signal. The measured signals are
therefore
a measure of the ALK1 kinase activity. Measurement takes place in a Perkin-
Elmer
top count apparatus or a Perkin-Elmer ViewLux instrument.
Material:
Enzyme: commercially available recombinant human ALK4 kinase (amino acids,
150-505), fused to GST at the N terminus, expressed by recombinant
baculoviruses in Sf21 insect cells (Upstate Biotechnology, Dundee, Scotland;
Cat#14-614MG), Lot#28232U; aliquots are stored at -80 C; diluted enzyme
working solution, 2.5 ng/pl ALK1 (in assay buffer) is freshly prepared and
stored on
ice until used.
Substrate: biotinylated bovine a-casein. Unbiotinylated casein from Sigma is
biotinylated by standard methods using a biotin-N-hydroxysuccinimide (NHS)
ester.
Substrate working solution: 0.83 pM ATP, 1.67 pM biotinylated a-casein, 7.4
nCi of
[y-331=]ATP/p1 in assay buffer
Assay plates: 384-well plates, small volume, white, Greiner (# 784075)
Flashplates: streptavidin-coated flashplates, Perkin Elmer (384-Well #
SPM410A)

CA 02620534 2008-02-28
SRG/US/53343 - 153 -
ALJ/TDS
=
Assay buffer: 50 mM Tris/HCI pH 8.0, 1 mM MnCl2, 1 mM OTT, 0.01% NP40, 0.5x
complete EDTA-free
Stop solution: 33.3 pM ATP, 33.3 mM EDTA, 0.07% Triton X-100 in PBS
Saturation solution for flashplates: 100 pM ATP, 0.2% Triton X-100 in PBS
Adhesive film for plates: Greiner (# 676080)
Description of assay
Protocol for a 5 pl assay (all steps are carried out at 20 C; a CyBi-well
pipettor and
a multidrop microdispensor is used for pipetting):
1. 50 nl or 250 nlof substance in 100% DMSO
2. addition of 3 pl of substrate working solution using a CyBi-Well pipettor
3. addition of 2 pl of enzyme working solution using a multidrop
microdispensor
Incubation at room temperature (20 C) for 45 min
4. addition of 15 pl of stop solution using a CyBi-Well pipettor
5. transfer of 18 pl of assay mixture into flashplates** using a CyBi-Well
pipettor
Incubation at room temperature for at least 3 h or at 4 C overnight in order
to allow
binding to the streptavidin-coated flashplates.
6. washing of the flashplates three times with 50 pl of PBS without Ca++ and
Mg++
each time
7. sealing of the plates with adhesive film
8. measurement in the top count (60 sec/well)
**Saturation of the flashplates: the flashplates are preincubated with 50 pl
of
saturation solution for at least 1 h. 18 pl of this solution are discarded
before 18 pl
of assay mixture are transferred into the flashplates
Final concentrations calculated for a reaction volume of 5 pl: 1 ng of
ALK1/well,
1 pM biotinylated oc-casein, 0.5 pM ATP; 22 nCi/well [7-33P]ATP, 1 mM MnC12;
1 mM DTT; 50 mM Tris-HCI, pH 8.0; 0.01% NP40; 0.5x complete EDTA-free; 1%
or 5% DMSO.

CA 02620534 2008-02-28
SRG/US/53343 - 154 -
ALJ/TDS
The data are normalized (enzyme reaction without inhibitor = 0% inhibition,
enzyme reaction in the presence of 10 mM EDTA = 100% inhibition) and IC50
values are calculated using a 4-parameter fit with the aid of an in-house
software.
ALK1 transactivation assay
In this case, HepG2 cell cultures are transiently transfected with an ALK1
plasnnid
(expression vector for the human ALK1 receptor) by known techniques. At the
same time, an ID1 reporter plasmid which 1.3 kB (-1370 to +86) of the ID1
promoter upstream of the luciferase gene is cotransfected. ID1 is a known
target
gene of ALK1 and is therefore transactivated by cotransfection with the ALK1
receptor. The specific transactivation is quantified by ("relative light
units", RLU)
which are detected depending on the luciferase. A commercially available kit
for
detecting luciferase, comprising the substrate luciferin, is used for this.
Material:
HepG2 cells (hepatocellular carcinoma), ATCC HB-8065
96 well culture plates 96 white (Packard # 6005680)
96 well plate polypropylene for compound dilution in DMSO
PBS-; PBS++, DMSO
DMEM Ham's F12 (Biochrom #F4815) with 10% FCS after dialysis, 1% PenStrep
and 200 mM Glutamine
OPTI MEM (Gibco #51985-026)
Fugene (Roche #1814443 1mL)
steadyliteHTS (Perkin Elmer# 6016981)
Experimental procedure:
Day 1: Seeding of the cells on 96-well plates

CA 02620534 2008-02-28
SRG/US/53343 - 155 -
ALJ/TDS
HepG2 cells are seeded on 96-well plates at a density of 7000 cell/well in
DMEM/HamsF12 + 5%FCS (+ 1% PIS, +1% Gln).
Day 2: Transfection of the cells
200 ng DNA: 100 ng ID1-luc (in pGL3basic, Promega)+ 5 ng ALK1wt (in
pcDNA3.1) + 95 ng pcDNA3.1 (empty vector, Invitogen)
0.4 pl of fugene
6 pl of OptiMEM
Fugene and OptiMEM are incubated at RT for 5 min. This mixture is incubated
with
the DNA at RT for 15 minutes.
The plate is then incubated under shaking conditions at RT for 1 hour. After 4
hours at 37 C, the supernatant is aspirated off, and medium (100 p1/well)
which
Day 3: RLU measurement
100 pl of luciferase substrate (steadyliteHTS, Packard) is added per well, and
the
Calculation of the IC50:
ALK1wt - DMSO control (without ALK1) = 100%

CA 02620534 2008-02-28
SRG/US/53343 - 156 -
ALJ/TDS
DU-145 proliferation assay
Firstly, DU-145 cells were seeded in a concentration of 200 cells per well in
a 96-
well microtiter plate (CulturPlate-96, flat bottom transparent) (volume of the
culture
medium: 100 pl; negative control in starvation medium) and grown under
culturing
conditions for 18 h. Then 100 pl of the culture medium were removed, and 100
pl
of substance solution (dilution in culture medium) were added. The cells are
incubated under culturing conditions for 72 h. After the end of the substance
treatment, 5 pl of an Alamar Blue labeling solution (Biosource cat # DAL 1100,
Lot # 143152SA; dissolved in culture medium) were added (in order to produce a
1:20 dilution) and the cells were grown under culturing conditions for a
further 3 h.
The proliferation rate was then analyzed by measurement in an FLx800
(fluorescence measuring instrument from BIO-TEK) at 528 nm and 590 nm in each
case.
Cell lines and cell culture
Human cell culture lines were used: DU-145 (prostate cell line ATCC No. HTB-
81).
All cell lines were grown in 175 cm2 culture bottles at 37 C, 5% CO2 and 95%
humidity and split 1:5 to 1:65 at 80% confluence in accordance with the
respective
rates of division. For this purpose, the cells were initially washed with 10
ml of PBS
and wetted with 2 ml of trypsin (Gibco). Excess trypsin was removed, and the
cells
were incubated at room temperature for 10 min. Complete detachment of the
treated cells was checked under the microscope. The cells were then taken up
in
culture medium and transferred in the appropriate volumetric ratio into new
cell
culture bottles.
DU-145 culture medium:
DMEM HAM's F-12 (from Biochrom AG, cat# F4815) + 1% P/S + 1% glutamin.e +
10% FCS (from Biochrom AG, Lot'0218G)
DU-145 starvation medium:
DMEM HAM's F-12 (from Biochrom AG, cat# F4815) + 1% P/S + 1% glutamine

CA 02620534 2008-02-28
SRG/US/53343 - 157 -
ALJ/TDS
Further proliferation assays
DNA-replicating cells can be labeled using bromodeoxy uiridine (BrdU) and used
as measure of the proliferation of eukaryotic cells. In this method, cells
which are in
the synthesis phase (S phase) incorporate the thymidine analog BrdU instead of
thymidine into the growing DNA chain. The replicated DNA is thus labeled with
the
modified nucleotide BrdU and can subsequently be detected with the aid of a
fluorophore-labeled anti-BrdU antibody. The method was used in order to
investigate the effect of substances on cellular proliferation.
Firstly, HeLa cells were seeded in a 96-well microtiter plate in a
concentration of
io 7500 cells per well (volume: 200 pl) and grown under culturing
conditions for 18 h.
Then 100 pl of the culture medium were removed, and 100 pl of substance
solution
(dilution in culture medium) were added. The cells were incubated under
culturing
conditions for 6 h, 18 h or 48 h. After the end of the substance treatment,
the BrdU-
labeling solution (dissolved in culture medium) was added (final concentration
of
is BrdU 10 pM), and the cells were grown under culturing conditions for a
further 3 h.
The BrdU-containing supernatant was then removed, and the cells were washed
with PBS. The cells were subsequently fixed with 4% strength formalin solution
(dissolved in PBS, 0.1% Triton-X-100) at 4 C for 18 h and washed three times
with
200 pl of PBS. In order to make the incorporated BrdU accessible for antibody
20 labeling, the DNA of the cells was digested with nuclease (GE/Amersham).
BrdU
was subsequently detected with the aid of a monoclonal anti-BrdU antibody
(GE/Amersham). For this purpose, the fixed cells were incubated with an
antibody/nuclease solution (50 p1/well) at 37 C for 45 min and then washed
three
times with 200 pl of PBS. The fluorescence labeling took place with a
fluorophore-
25 labeled second antibody which binds to the anti-BrdU antibody. The
chromatin of
the cell nuclei was stained with Hoechst 33342.
In each case 9 image sections per well were recorded in the various
fluorescence
channels using an automated microscope (Discovery-1, Molecular Devices), and
the BrdU incorporation and the proliferation rate were analyzed by means of a
30 high-content analysis (HCA) method.

CA 02620534 2008-02-28
SRG/US/53343 - 158 -
ALJ/TDS
Cell lines and cell culture
Human cell culture lines were used: HeLa (from cervical carcinoma), PC3 (from
prostatic carcinoma) and MCF-7 (from carcinoma of the breast). In addition,
CHO
cells (from Chinese hamster ovaries) were cultured.
All cell lines were grown in 175 cm2 culture bottles at 37 C, 5% CO2 and 95%
humidity and split 1:5 to 1:65 at 80% confluence in accordance with the
respective
rates of division. For this purpose, the cells were initially washed with 10
ml of PBS
and wetted with 2 ml of trypsin (Gibco). Excess trypsin was removed, and the
cells
were incubated at room temperature for 10 min. Complete detachment of the
io treated cells was checked under the microscope. The cells were then
taken up in
culture medium and transferred in the appropriate volumetric ratio into new
cell
culture bottles.
HeLa culture medium:
Dulbecco's medium (Gibco), 2 mM glutamine (Gibco), 100 Wm! penicillin (Gibco),
100 pg/ml streptomycin (Gibco) and 10% (v/v) fetal calf serum (PAA)
PC3 culture medium:
RPM' 1640 medium (Gibco), 2 mM glutamine (Gibco), 100 U/ml penicillin (Gibco),
100 pg/ml streptomycin (Gibco) and 10% (v/v) fetal calf serum (PAA)
MCF-7 culture medium:
RPM' 1640 medium (Gibco), 2 mM glutamine (Gibco), 100 U/ml penicillin (Gibco),
100 pg/ml streptomycin (Gibco) and 10% (v/v) fetal calf serum (PAA), 0.1 nM
estradiol (Sigma) and 0.2 Wm! insulin (Sigma)
CHO culture medium:
Ham's F12 medium (PAA), 2 mM glutamine (Gibco), 100 U/m1 penicillin (Gibco),
100 pg/ml streptomycin (Gibco) and 3% (v/v) fetal calf serum (PM)

CA 02620534 2008-02-28
SRG/US/53343 - 159 -
ALJffDS
Further prior art
Further prior art is formed by the following publications and the literature
cited in
these publications:
DE 3542661 EP 1040818
EP 979231 B1 EP 1040817
WO 02/066481 EP 998908
WO 2005/066177 EP 966951
WO 2004/087153 EP 926149
WO 98/03510 WO 99/66894
WO 99/38868 WO 99/66893
WO 2003/041670 WO 99/66892
WO 2004/085409 WO 99/11230
WO 2004/058755 WO 99/66891
WO 2004/111056 WO 97/49378
WO 2005/003101 WO 98/54093
W003/091256 W02004/052315
WO 2004/087707 WO 2004/089416
WO 96/35690 WO 2004/089471
WO 2004/085409 US 2005/0282827
WO 2003/006471 US 2004/0209878
WO 2005/085252 US 2002/0041880
W02005/003101
Gorup et al., Tetrahedron 30 (1974), Byth et al. Bioorganic & Medicinal
2251-2256 Chemistry Letters 14 (2004) 2249-2252
Polanc et al., J. Heterocyclic Chemistry Watanabe et al, Synthesis 11 (1977),
(1973), 565-567 761-763
Bioorganic & Medicinal Chemistry Bioorganic & Medicinal Chemistry
Letters 2006,1353 Letters 2005,1943
Bioorganic & Medicinal Chemistry Journal of Medicinal Chemistry 2005,
Letters 2004 ,6095 7604

CA 02620534 2008-02-28
SRG/US/53343 - 160 -
ALJ/TDS
Priorities of the present application:
The present patent application claims the priority of German patent
application
DE 10 2005 042 742.1 (date of filing: Sept. 2,2005), and it also claims all
the
advantages of filing of the US patent application 60/713 333 (date of filing:
Sept. 2,
2005, provisional application).
The independent claims of the priority application read as follows:
1. A compound of the formula I
Formel
R1, 14
N N.
R2 A
where
is aryl or heteroaryl;
A and B are identical or different and are selected from the group consisting
of
i) H, Hal, -OH, -NR3R4, -CN, or -NO2,
ii) optionally mono- or poly-Hal-, -OH-, C3-C6-heterocycloalkyl-, -NR3R4-,
or -(C0)-NR3-L-substituted C1-C6-alkyl, C1-C6-alkoxy, C3-C6-cycloalkyl
or C3-C6-heterocycloalkyl, where the C3-C6-heterocycloalkyl may
comprise in the ring optionally one or more nitrogen, oxygen and/or sulfur
atoms and/or one or more -(00)- or -(SO2)- groups and/or one or more
double bonds, and
iii) -NR3(C0)-L, -NR3(C0)-NR3-L, -(C0)-R6, -0-(CH2)p-R6,
-(C0)-(NR3)-L, -NR3(CS)-NR3R4 or -0-(CH2)p-aryl, where the
substituents in the case of polysubstitution may be identical or different,

CA 02620534 2008-02-28
SRG/US/53343 - 161 -
ALJ/TDS
A and B in addition or alternatively to the aforementioned definition together
form
a Q-fused C5-C7-cycloalkyl or C5-C7-heterocycloalkyl ring, where the
latter comprises at least one oxygen or one nitrogen atom in the ring,
and may optionally comprise additionally in the ring one or more oxygen,
nitrogen or sulfur atoms and/or one or more ¨(CO)- or ¨(SO2)- groups
and/or optionally one or more double bonds,
is 0 to 4,
is optionally mono- or poly-C1-C6-alkyl-, C1-C6-hydroxyalkoxy-, C1-C6-
alkoxyalkoxy, C3-C6-heterocycloalkyl-, or -NR3R4-substituted C1-C6-alkyl, or
C3-C6-cycloalkyl or C3-C6-heterocycloalkyl, where the C3-C6
heterocycloalkyl may comprise in the ring optionally one or more nitrogen,
oxygen and/or sulfur atoms and/or one or more -(CO)- or -(SO2)- groups
and/or one or more double bonds;
R1 and R2 are identical or different and are selected from the group
consisting of j) ¨H
and jj) optionally mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-
alkoxy-, C1-C6-hydroxyalkyl-, C3-C6-cycloalkyl-, C3-C6 heterocycloalkyl-,
C2-C6-alkynyl-, aryl-, aryloxy-, heteroaryl-, -S-C1-C6-alkyl-, -(C0)-R6-,
-NR3R4-, -NR3(C0)-L- or -NR3COOR7-substituted C1-C6-alkyl, C1-C6-
alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-
heterocycloalkyl, aryl or heteroaryl, where the C3-C6-heterocycloalkyl may
optionally comprise in the ring one or more nitrogen, oxygen and/or sulfur
atoms and/or one or more -(CO)- or -SO2- groups and/or one or more
double bonds, and where the substituents in the case of polysubstitution
may be identical or different;
R1 and R2 in addition or alternatively to the aforementioned definition may
together form a C3-C6-heterocycloalkyl ring which comprises at least
one nitrogen atom in the ring and may optionally comprise additionally
in the ring one or more nitrogen, oxygen or sulfur atoms and/or one or
more -(CO)- or ¨(SO2)- groups and/or optionally one or more double

CA 02620534 2008-02-28
SRG/US/53343 - 162 -
ALJ/TDS
bonds, where the ring formed by R1 and R2 may be optionally
substituted one or more times by -CN, -Hal, -OH, C1-C6-alkyl, C3-C6-
cycloalkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxyalkyl, -NR3R4, -CONR6R7,
-(C0)-R6 or -COOR7 and/or by optionally mono- or poly-Hal-, C1-C6-
alkoxy- or -(C0)-R6-substituted aryl or heteroaryl, where the
substituents in the case of polysubstitution may be identical or
different;
R3 and R4 are identical or different and are selected from the group
consisting of
j) -H, and jj) optionally mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-
alkoxy-, C1-C6-hydroxyalkyl-, C3-C6-cycloalkyl-, C3-C6 heterocycloalkyl-,
C2-C6-alkynyl-, aryl-, aryloxy-, heteroaryl-, -NR6R7-, -CONR6R7-, -(C0)-
R6- or -COOR7-substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-
C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl,
where the C3-C6-heterocycloalkyl may comprise in the ring optionally one
or more nitrogen, oxygen and/or sulfur atoms and/or one or more -(C0)-
or -SO2- groups and/or one or more double bonds, and where the
substituents in the case of polysubstitution may be identical or different;
R3 and R4 in addition to the aforementioned definition may together form a
C3-C6-heterocycloalkyl ring which comprises at least one nitrogen
atom in the ring and may optionally comprise additionally in the ring
one or more nitrogen, oxygen or sulfur atoms and/or one or more
-(00)- or ¨(SO2)- groups and/or optionally one or more double bonds,
where the ring formed by R3 and R4 may be optionally substituted one
or more times by -CN, -Hal, -OH, C1-C6-alkyl, C3-C6-cycloalkyl, C1-
C6-hydroxyalkyl, C1-C6-alkoxyalkyl, or by -NR6R7, -CONR6R7, -(C0)-
R6 or -COOR7 and/or by optionally mono- or poly-Hal-, C1-C6-alkoxy- or
-(C0)-R6-substituted aryl or heteroaryl, where the substituents in the
case of polysubstitution may be identical or different;
R6 and R7 are identical or different and are selected from the group
consisting of
j) -H and jj) optionally mono- or poly-Hal-, -OH-, -CN-substituted C1-C6-

CA 02620534 2008-02-28
SRG/US/53343 -163-
ALJ/TDS
alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-
C6-heterocycloalkyl, aryl or heteroaryl, where the C3-C6-heterocycloalkyl
may comprise in the ring optionally one or more nitrogen, oxygen and/or
sulfur atoms and/or one or more -(CO)- or -SO2- groups and/or one or
more double bonds, and where the substituents in the case of
polysubstitution may be identical or different,
and the isomers, diastereomers, enantiomers and salts thereof.
2. The compound as claimed in claim 1, where R1 and R2 are identical or
different
and selected from the group consisting of j) ¨H and jj) optionally mono- or
poly-
Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-hydroxyalkyl-, C3-C6-
cycloalkyl-, C3-C6 heterocycloalkyl-, C2-C6-alkynyl-, aryl-, aryloxy-,
heteroaryl-, -S-C1-C6-alkyl, -(C0)-R6-, -NR3R4-, -NR3(C0)-L- or -NR3COOR7-
substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-
cycloalkyl, C3-C6-heterocycloalkyl, where the C3-C6-heterocycloalkyl may
optionally comprise in the ring one or more nitrogen, oxygen and/or sulfur
atoms and/or one or more -(C0)- or -SO2- groups and/or one or more double
bonds, where the substituents may in the case of polysubstitution be identical
or different, and where R1 and R2 in addition or alternatively to the
preceding
definition may together form a C3-C6-heterocycloalkyl ring which comprises
at least one nitrogen atom in the ring and may optionally additionally
comprise in the ring one or more nitrogen, oxygen or sulfur atoms and/or
one or more -(CO)- or ¨(SO2)- groups and/or optionally one or more double
bonds, where the ring formed by R1 and R2 may be optionally substituted
one or more times by -CN, -Hal, -OH, C1-C6-alkyl, C3-C6-cycloalkyl,
Cl-C6-hydroxyalkyl, Cl -C6-alkoxyalkyl, -NR3R4, -CONR6R7, -(C0)-R6 or
-COOR7 and/or by optionally mono- or poly-Hal-, C1-C6-alkoxy- or -(C0)-R6-
substituted aryl or heteroaryl, where the substituents may in the case of
polysubstitution be identical or different.
3. The compound as claimed in claim 1 or 2, wherein R1 and R2 are identical
or
different and selected from the group consisting of j) ¨H and jj) optionally

CA 02620534 2008-02-28
SRG/US/53343 - 164 -
A L.I/TD S
mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-
hydroxyalkyl-, C3-C6-cycloalkyl-, C3-C6 heterocycloalkyl-, C2-C6-alkynyl-,
aryloxy-, -S-C1-C6-alkyl-, -(C0)-R6-, -NR3R4-, -NR3(C0)-L- or -NR3COOR7-
substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-
cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl, where the C3-C6-
heterocycloalkyl may optionally comprise in the ring one or more nitrogen,
oxygen and/or sulfur atoms and/or one or more -(CO)- or -SO2- groups and/or
one or more double bonds, where the group aryl or heteroaryl defined in jj)
may be substituted as long as alkyl is not involved, where the substituents
may
in the case of polysubstitution be identical or different, and where R1 and R2
in
addition or alternatively to the preceding definition may together form a
C3-C6-heterocycloalkyl ring which comprises at least one nitrogen atom in
the ring and may optionally additionally comprise in the ring one or more
nitrogen, oxygen or sulfur atoms and/or one or more -(C0)- or -(S02)-
groups and/or optionally one or more double bonds, where the ring formed
by R1 and R2 is optionally substituted one or more times by -CN, -Hal, -OH,
C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxyalkyl,
-NR3R4, -CONR6R7, -(C0)-R6 or -COOR7 and/or by optionally mono- or poly-
Hal-, C1-C6-alkoxy- or -(C0)-R6-substituted aryl or heteroaryl, where the
substituents may in the case of polysubstitution be identical or different.
4. The compound as claimed in claim 3, where Q is -OH-, -Hal-, -CN-,
alkyl-,
-0R6- or -NR3R4-substituted phenyl, pyridyl, pyrimidinyl, thiophenyl, furyl,
imidazolyl, or pyrazolyl.
5. The compound as claimed in claim 4, where R1 and R2 are identical or
different
and selected from the group consisting of -H, NR3R4-substituted C1-C4-alkyl,
optionally additionally substituted one or more times by -Hal, -OH, -CN, C1-C6-
alkyl, C1-C6-alkoxy, C1-C6-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6
heterocycloalkyl, C2-C6-alkynyl, aryl, aryloxy, heteroaryl, -S-C1-C6-alkyl,
-(C0)-R6, -NR3(C0)-L, or -NR3COOR7, where R3 and R4 may optionally,
identically or differently, be C1-C6-alkyl, where R3 and R4 may together form
a

CA 02620534 2008-02-28
SRG/US/53343 - 165 -
ALJ/TDS
C3-C6-heterocycloalkyl ring which comprises at least one nitrogen atom in the
ring and may optionally additionally comprise in the ring one or more
nitrogen,
oxygen or sulfur atoms and/or one or more -(C0)- or -(SO2)- groups and/or
optionally one or more double bonds, and where R6 and R7 is identically or
differently -H, -OH, C1-C6-alkoxy, or C1-C3-alkyl.
6. The compound as claimed in any of claims 4, where R1 is selected from
the
group consisting of ¨H and C1-C3-alkyl, where R2 is selected from the group
consisting of NR3R4-substituted C3-C4 alkyl, optionally additionally mono- or
poly-
Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-hydroxyalkyl-, C3-C6-
cycloalkyl-, C3-C6 heterocycloalkyl-, C2-C6-alkynyl-, aryl-, aryloxy-,
heteroaryl-,
-S-C1-C6-alkyl-, -(C0)-R6-, -NR3(C0)-L- or -NR3COOR7-substituted, where R3
and R4 are identically or differently optionally mono- or poly-Hal-, -OH-, -CN-
,
C1-C6-alkyl-, C1-C6-alkoxy-, C1-C6-hydroxyalkyl-, C3-C6-cycloalkyl-, C3-C6
heterocycloalkyl-, C2-C6-alkynyl-, aryl-, aryloxy-, heteroaryl-, -NR6R7-,
-CONR6R7-, -(C0)-R6- or -COOR7-substituted C1-C6-alkyl, where R3 and R4
may together form a C3-C6-heterocycloalkyl ring which comprises at least one
nitrogen atom in the ring and may optionally additionally comprise in the ring
one or more nitrogen, oxygen or sulfur atoms and/or one or more -(CO)- or
-(SO2)- groups and/or optionally one or more double bonds, and where R6
and R7 is identically or differently -H, -OH, C1-C6-alkoxy, or C1-C3 alkyl.
7. The compound as claimed in claim 1, namely:
(3-phenylimidazo[1,2-14yridazin-6-y1)-(3-pyrrolidin-l-ylpropyl)amine
(3-morpholin-4-ylpropyI)-(3-phenylimidazo[1,2-b]pyridazin-6-yl)amine
(3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-y1)-(3-pyrrolidin-1-
ylpropyl)amine
(3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-y1)-(3-morpholin-4-
ylpropyl)amine
[3-(1-methyl-1 H-pyrazol-4-yl)imidazo[1 , 2-b]pyridazi n-6-yl]pyrid in-3-
ylmethylamine

CA 02620534 2008-02-28
SRG/US/53343 - 166 -
A LJ/TDS
(3-phenylimidazo[1 ,2-1D]pyridazin-6-yl)pyridin-3-ylmethylamine
(3-imidazol-1-ylpropy1)-(3-phenylimidazo[1 ,2-1Apyridazin-6-yl)amine
(4-fluorobenzyI)-(3-phenylimidazo[1 ,2-1D]pyridazin-6-y0amine
cyclohexylmethyl(3-phenylimidazo[1,2-b]pyridazin-6-y1)amine
(2,4-difluorobenzy1)-(3-phenylimidazo[1,2-13]pyridazin-6-y1)amine
[3-(5-methy1-1H-pyrazol-4-yl)propyl]-(3-phenylimidazo[1,2-b]pyridazin-6-
yl)amine
142-(3-phenylimidazo[1 ,2-b]pyridazin-6-ylamino)ethyllimidazolidin-2-one
(2-morpholin-4-ylethyl))-(3-phenylimidazo[1 ,2-b]pyridazin-6-yl)amine
N*1 ,N*1*-diethyl-N*4-(3-phenylimidazo[1,2-b]pyridazin-6-y1)pentane-1,4-
diamine
N,N-diethyl-N"-(3-phenylimidazo[1,2-Npyridazin-6-y1)propane-1,3-diamine
(3-phenylimidazo[1,2-b]pyridazin-6-y1)-(2-pyrrolidin-1-ylethyl)amine
[3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yllpyridin-3-ylmethylamine
[3-(3-chlorophenyl)imidazo[1 ,2-b]pyridazin-6-y1]-(3-imidazol-1-
ylpropyl)amine
3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-y1)-(4-fluorobenzyl)amine
3-(3-chlorophenypimidazo[1,2-Npyridazin-6-yl)cyclohexylmethylamine
3-(3-chlorophenypimidazo[1,2-b]pyridazin-6-y1)-(2,4-difluorobenzyl)amine
1-1243-(3-phenypimidazo[1,2-b]pyridazin-6-ylamino]ethyl}imidazolidin-2-
one
N*4*-[3-(3-chlorophenypimidazo[1,2-b]pyridazin-6-y1]-N*1*,N*1*-
diethylpentane-1,4-diamine
N"-[3-(3-chlorophenypimidazo[1 ,2-b]pyridazin-6-y11-N,N-diethylpropane-
1 ,3-diamine
[3-(3-chlorophenyl)imidazo[1 ,2-b]pyridazin-6-yI]-(2-pyrrolidin-1 -
ylethypamine

CA 02620534 2008-02-28
SRG/US/53343 - 167 -
ALJ/TDS
(3-imidazol-1-ylpropy1)43-(1 -methyl-I H-pyrazol-4-yl)imidazo[1,2-
b]pyridazin-6-yliamine
(4-fluorobenzyl)-[341 -methyl-I H-pyrazol-4-yl)imidazo[1,2-13]pyridazin-6-
yljamine
cyclohexylmethy11341-methyl-1 H-pyrazol-4-yl)imidazo[1,2-Npyridazin-6-
yl]amine
(2,4-difluorobenzy1)4341 -methyl-I H-pyrazol-4-yl)imidazo[1,2-1Apyridazin-
6-yl]amine
[341-methy1-1 H-pyrazol-4-Aimidazo[1,2-1Apyridazin-6-y1H5-methyl-1 H-
pyrazol-4-yl)propyljamine
1 421341 -methyl-I H-pyrazol-4-yl)imidazo[1 ,2-b]pyridazin-6-
ylaminolethyl}imidazolidin-2-one
(341-methy1-1 H-pyrazol-4-yl)imidazo[1,2-13]pyridazin-6-y1)-(2-morpholin-4-
ylethypamine
N*1 ,N*1*-diethyl-N*44341 -methyl-1 H-pyrazol-4-yl)imidazo[1,2-
b]pyridazin-6-yl]pentane-1 ,4-diamine
N,N-diethyl-N '4341-methyl-I H-pyrazol-4-yl)imidazo[1 ,2-b]pyridazin-6-
yl]propane-1,3-diamine
[3-( 1 -methyl-I H-pyrazol-4-yl)imidazo[1 ,2-b]pyridazin-6-yI]-(2-pyrrolidin-1-
ylethyl)amine
pyridin-3-ylmethy143-thiophen-3-ylimidazo[1,2-b]pyridazin-6-yl)amine
(4-fluorobenzy1)-(3-thiophen-3-ylimidazo[1,2-1Apyridazin-6-yl)amine
cyclohexylmethy1(3-thiophen-3-ylimidazo[1,2-b]pyridazin-6-yl)amine
(2,4-difluorobenzyI)-(3-thiophen-3-ylimidazo[1 ,2-b]pyridazin-6-ypamine
[345-methyl-1 H-pyrazol-4-yl)propyl]-(3-thiophen-3-ylimidazo[1 ,2-
b]pyridazin-6-yl)amine
1 [243-thiophen-3-ylimidazo[1 ,2-b]pyridazin-6-ylamino)ethyl]imidazolidin-
2-one
(2-morpholin-4-ylethyl)-(3-thiophen-3-ylimidazo[1,2-1Apyridazin-6-yl)amine

CA 02620534 2008-02-28
SRG/US/53343 - 168-
ALJ/TDS
N*1 ,N*1*-diethyl-N*443-thiophen-3-ylimidazo[l ,2-b]pyridazin-6-
yl]pentane-1,4-diamine
N,N-diethyl-N"-(3-thiophen-3-ylimidazo[1,2-b]pyridazin-6-yl]propane-1,3-
diamine
(2-pyrrolidin-l-ylethyl)-(3-thiophen-3-ylimidazo[1,2-14yridazin-6-y1)amine
8. A method for preparing a compound as claimed in any of claims 1 to 7, with
the following stages of the method:
Al) 3-amino-6-halopyrazine is reacted with chloractetaldehyde to give 6-
haloimidazo[1,2-b]pyridazine,
pa A2) the product from stage Al is reacted with N-bromosuccinimide to give
a 3-
bromo-6-haloimidazo[l ,2-b]pyridazine,
A3) the product from stage A2 is converted by reaction with a compound NHR1R2
in a Buchwald-Hartwig cross-coupling reaction into a (3-bromoimidazo[1,2-
b]pyridazin-6-y1)-(R1)-(R2)-amine,
A4) the product from stage A3 is reacted for example with a boronic acid which
is
optionally substituted by the radicals A and B to give the compound
according to the general formula I,
or
B1) 3-amino-6-halopyrazine is reacted with chloractetaldehyde to give 6-
haloimidazo[1,2-b]pyridazine,
B2) the product from stage B1 is reacted with N-bromosuccinimide to give a 3-
bromo-6-haloimidazo[1,2-b]pyridazine,
B3) the product from stage B2 is reacted for example with a boronic acid which
is
optionally substituted by the radicals A and B to give the compound
according to the general formula II,

CA 02620534 2008-02-28
SRG/US/53343 - 169 -
ALJ/TDS
B4) the product from stage B3 is converted by reacting with a compound NHR1R2
in a Buchwald-Hartwig cross-coupling reaction into the compound according
to the general formula I,
or
Cl) 3-amino-6-halopyrazine is reacted with chloractetaldehyde to give 6-
haloimidazo[1,2-b]pyridazine,
C2) the product from stage Cl is converted by reacting with a compound NHR1R2
in a Buchwald-Hartwig cross-coupling reaction into an imidazo[1,2-
b]pyridazin-6-y1)-(R1)-(R2)-amine,
C3) the product from stage C2 is reacted with N-bromosuccinimide to give a (3-
bromoimidazo[1,2-b]pyridazin-6-yI)-(R1)-(R2)-amine,
C4) the product from stage C3 is reacted for example with a boronic acid which
is
optionally substituted by the radicals A and B to give the compound
according to the general formula I.
9. The use of a compound as claimed in any of claims 1 to 7 for producing a
pharmaceutical composition.
10. The use of a compound as claimed in any of claims 1 to 7 for inhibiting a
cellular kinase, in particular a kinase from the group of the protein kinase C
family such as, for example, PKC theta, delta, iota, alpha and zeta.
11. The use of a compound as claimed in any of claims 1 to 7 for producing a
pharmaceutical composition for the treatment or for the prophylaxis of a
disorder which is associated with overexpression or mutation of a cellular
kinase, in particular a cellular kinase according to claim 10.
12. The use as claimed in claim 9, where the disorder is a disorder from the
group consisting of "epidermal hyperproliferation such as psoriasis,
Alzheimer's, autoinflammatory disorders, Crohn's disease, exaggerated

CA 02620534 2008-02-28
SRG/US/53343 - 170 -
ALJ/TDS
immune response, contact dermatitis, atopic dermatitis, multiple sclerosis,
ALS, diabetes, asthma".
13. The use as claimed in claim 9 for modulating, in particular reducing, an
immune response, for example after a transplantation has taken place to
avoid rejection of an organ.
14. A method for producing a pharmaceutical composition, where a
physiologically effective dose of a compound as claimed in any of claims 1 to
7 is mixed with at least one pharmaceutical excipient, and a dosage form is
manufactured.
io 15. A method for the treatment or prophylaxis of a disorder which is
associated
with overexpression or mutation of a cellular kinase, in particular a disorder
according to claim 12, where a pharmaceutical composition comprising a
physiologically effective dose of a compound as claimed in any of claims 1 to
7 is administered to a person suffering from or under threat of suffering from
the disorder.
16. An intermediate according to formula I la
R1,N,-rf-N-N-.N?
R2
General formula Ila
where
Y is replaced by -H or -Hal,
R1 and R2 are identical or different and selected from the group consisting of
j) ¨H and
jj) optionally mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-alkoxy-,
C1-C6-hydroxyalkyl-, C3-C6-cycloalkyl-, C3-C6 heterocycloalkyl-, C2-C6-

CA 02620534 2008-02-28
SRG/US/53343 - 171 -
ALJ/TDS
alkynyl-, aryl-, aryloxy-, heteroaryl-, -S-C1-C6-alkyl-, -(C0)-R6-, -NR3R4-,
-NR3(C0)-L- or -NR3COOR7-substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-
alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or
heteroaryl, where the C3-C6-heterocycloalkyl may optionally comprise in
the ring one or more nitrogen, oxygen and/or sulfur atoms and/or one or
more -(CO)- or -SO2- groups and/or one or more double bonds, and
where the substituents in the case of polysubstitution may be identical or
different;
R1 and R2 in addition or alternatively to the preceding definition may
together
io form a C3-C6-heterocycloalkyl ring which comprises at least one
nitrogen atom in the ring and may optionally additionally comprise in
the ring one or more nitrogen, oxygen or sulfur atoms and/or one or
more -(00)- or -(SO2)- groups and/or optionally one or more double
bonds, where the ring formed via R1 and R2 may be optionally
substituted one or more times by -CN, -Hal, -OH, C1-C6-alkyl, C3-C6-
cycloalkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxyalkyl, -NR3R4, -CONR6R7,
-(C0)-R6 or -COOR7 and/or by optionally mono- or poly-Hal-, C1-C6-
alkoxy- or -(C0)-R6-substituted aryl or heteroaryl, where the
substituents in the case of polysubstitution may be identical or
different;
R3 and R4 are identical or different and selected from the group consisting of
j)¨H
and jj) optionally mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-
alkoxy-, C1-C6-hydroxyalkyl-, C3-C6-cycloalkyl-, C3-C6 heterocycloalkyl-,
C2-C6-alkynyl-, aryl-, aryloxy-, heteroaryl-, -NR6R7-, -CONR6R7-, -(C0)-
R6- or -COOR7-substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-
C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl,
where the C3-C6-heterocycloalkyl may optionally comprise in the ring one
or more nitrogen, oxygen and/or sulfur atoms and/or one or more -(C0)-
or -SO2- groups and/or one or more double bonds, and where the
substituents in the case of polysubstitution may be identical or different;

CA 02620534 2008-02-28
SRG/US/53343 - 172 -
ALJ/TDS
R3 and R4 in addition or alternatively to the preceding definition may
together
form a C3-C6-heterocycloalkyl ring which comprises at least one
nitrogen atom in the ring and may optionally additionally comprise in
the ring one or more nitrogen, oxygen or sulfur atoms and/or one or
more -(CO)- or -(SO2)- groups and/or optionally one or more double
bonds, where the ring formed by R3 and R4 may optionally be
substituted one or more times by -CN, -Hal, -OH, C1-C6-alkyl, C3-C6-
cycloalkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxyalkyl or by -NR6R7,
-CONR6R7, -(C0)-R6 or -COOR7 and/or by optionally mono- or poly-
Hal-, C1-C6-alkoxy- or -(C0)-R6-substituted aryl or heteroaryl, where
the substituents in the case of polysubstitution may be identical or
different;
R6 and R7 are identical or different and selected from the group consisting of
j)¨H
and jj) optionally mono- or poly-Hal-, -OH-, -CN-substituted C1-C6-alkyl, C1-
C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-
heterocycloalkyl, aryl or heteroaryl, where the C3-C6-heterocycloalkyl may
optionallyt comprise in the ring one or more nitrogen, oxygen and/or sulfur
atoms and/or one or more -(CO)- or -SO2- groups and/or one or more
double bonds, and where the substituents in the case of polysubstitution
may be identical or different,
and the isomers, diastereomers, enantiorners and salts thereof.
17. An intermediate according to general formula lib

CA 02620534 2008-02-28
SRG/US/53343 - 173 -
ALJ/TDS
X N
0 A
General formula Ilb
Q is aryl or heteroaryl,
A and B are identical or different and selected from the group consisting of
i) H,
Hal, -OH, -NR3R4, -CN or -NO2,
ii) optionally mono- or poly-Hal-, -OH-, C3-C6-heterocycloalkyl-, -NR3R4-,
or -(C0)-NR3-L-substituted C1-C6-alkyl, C1-C6-alkoxy, C3-C6-cycloalkyl
to or C3-C6-heterocycloalkyl, where the C3-C6-heterocycloalkyl may
optionally comprise in the ring one or more nitrogen, oxygen and/or sulfur
atoms and/or one or more -(CO)- or -(SO2)- groups and/or one or more
double bonds, and
iii) -NR3(C0)-L, -NR3(C0)-NR3-L, -(C0)-R6, -0-(CH2)p-R6,
-(C0)-(NR3)-L, -NR3(CS)-NR3R4, or -0-(CH2)p-aryl, where the
substituents in the case of polysubstitution may be identical or different,
A and B in addition or alternatively to the preceding definition together form
a Q-
fused C5-C7-cycloalkyl or C5-C7-heterocycloalkyl ring, where the latter
comprises at least one oxygen or nitrogen atom in the ring and may
optionally additionally comprise in the ring one or more oxygen, nitrogen
or sulfur atoms and/or one or more ¨(C0)- or ¨(SO2)- groups and/or
optionally one or more double bonds,
is 0 to 4,
is optionally mono- or poly-C1-C6-alkyl-, C1-C6-hydroxyalkoxy-, C1-C6-
alkoxyalkoxy-, C3-C6-heterocycloalkyl- or -NR3R4-substituted C1-C6-alkyl or
C3-C6-cycloalkyl or C3-C6-heterocycloalkyl, where the C3-C6

CA 02620534 2008-02-28
SRG/US/53343 - 174-
ALJ/TDS
heterocycloalkyl may optionally comprise in the ring one or more nitrogen,
oxygen and/or sulfur atoms and/or one or more -(CO)- or -(SO2)- groups
and/or one or more double bonds;
X is chlorine, bromine, 0-S02-CF3 or 0-S02-C4F9;
R3 and R4 are identical or different and selected from the group consisting of
j) ¨H,
and jj) optionally mono- or poly-Hal-, -OH-, -CN-, C1-C6-alkyl-, C1-C6-
alkoxy-, C1-C6-hydroxyalkyl-, C3-C6-cycloalkyl-, C3-C6 heterocycloalkyl-,
C2-C6-alkynyl-, aryl-, aryloxy-, heteroaryl-, -NR6R7-, -CONR6R7-, -(C0)-
R6- or -COOR7-substituted C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-
C6-alkynyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, aryl or heteroaryl,
where the C3-C6-heterocycloalkyl may optionally comprise in the ring one
or more nitrogen, oxygen and/or sulfur atoms and/or one more -(C0)- or
-SO2- groups and/or one or more double bonds, and where the
substituents in the case of polysubstitution may be identical or different;
is R3 and R4 may in addition or alternatively to the preceding definition
together
form a C3-C6-heterocycloalkyl ring which comprises at least one
nitrogen atom in the ring and may optionally additionally comprise in
the ring one or more nitrogen, oxygen or sulfur atoms and/or one or
more -(CO)- or -(SO2)- groups and/or optionally one or more double
bonds, where the ring formed via R3 and R4 may optionally be
substituted one or more times by -CN, -Hal, -OH, C1-C6-alkyl, C3-C6-
cycloalkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxyalkyl, or by -NR6R7,
-CONR6R7, -(C0)-R6 or -COOR7 and/or by optionally mono- or poly-
Hal-, C1-C6-alkoxy- or -(C0)-R6-substituted aryl or heteroaryl, where
the substituents may in the case of polysubstitution be identical or
different;
R6 and R7 are identical or different and selected from the group consisting of
j)¨H
and jj) optionally mono- or poly-Hal-, -OH-, -CN-substituted C1-C6-alkyl, C1-
C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-

CA 02620534 2008-02-28
SRG/US/53343 - 175 -
ALJ/TDS
heterocycloalkyl, aryl or heteroaryl, where the C3-C6-heterocycloalkyl may
optionally comprise in the ring one or more nitrogen, oxygen and/or sulfur
atoms and/or one or more -(CO)- or -SO2- groups and/or one or more
double bonds, and where the substituents in the case of polysubstitution
may be identical or different
and the isomers, diastereomers, enantiomers and salts thereof.