U.S. patent application number 15/706073 was filed with the patent office on 2018-05-10 for novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders.
This patent application is currently assigned to GALAPAGOS NV. The applicant listed for this patent is GALAPAGOS NV. Invention is credited to Xavier Marie BOCK, Reginald Christophe Xavier BRYS, Nicolas DESROY, Bertrand HECKMANN, Christopher Gaetan HOUSSEMAN, Agnes Marie JONCOUR, Christophe PEIXOTO.
Application Number | 20180127425 15/706073 |
Document ID | / |
Family ID | 50942280 |
Filed Date | 2018-05-10 |
United States Patent
Application |
20180127425 |
Kind Code |
A1 |
DESROY; Nicolas ; et
al. |
May 10, 2018 |
NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE
TREATMENT OF INFLAMMATORY DISORDERS
Abstract
The present invention discloses compounds according to Formula
I: ##STR00001## Wherein R.sup.1a, R.sup.1b, R.sup.2, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, W, X, Y, Z, Cy, and the
subscript a are as defined herein. The present invention relates to
compounds inhibiting autotaxin (NPP2 or ENPP2), methods for their
production, pharmaceutical compositions comprising the same, and
methods of treatment using the same, for the prophylaxis and/or
treatment of diseases involving fibrotic diseases, proliferative
diseases, inflammatory diseases, autoimmune diseases, respiratory
diseases, cardiovascular diseases, neurodegenerative diseases,
dermatological disorders, and/or abnormal angiogenesis associated
diseases by administering the compound of the invention.
Inventors: |
DESROY; Nicolas;
(Romainville, FR) ; HECKMANN; Bertrand;
(Romainville, FR) ; BRYS; Reginald Christophe Xavier;
(Mechelen, BE) ; JONCOUR; Agnes Marie;
(Romainville, FR) ; PEIXOTO; Christophe;
(Romainville, FR) ; BOCK; Xavier Marie;
(Romainville, FR) ; HOUSSEMAN; Christopher Gaetan;
(Romainville, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GALAPAGOS NV |
Mechelen |
|
BE |
|
|
Assignee: |
GALAPAGOS NV
Mechelen
BE
|
Family ID: |
50942280 |
Appl. No.: |
15/706073 |
Filed: |
September 15, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14898327 |
Dec 14, 2015 |
9796719 |
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PCT/EP2014/062241 |
Jun 12, 2014 |
|
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15706073 |
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61836831 |
Jun 19, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4985 20130101;
A61K 31/5383 20130101; A61P 11/00 20180101; A61K 31/541 20130101;
A61P 17/00 20180101; A61P 25/28 20180101; A61K 31/5377 20130101;
A61K 31/5025 20130101; A61K 45/06 20130101; A61K 31/551 20130101;
A61P 29/00 20180101; C07D 487/04 20130101; A61K 31/506 20130101;
A61P 37/06 20180101; A61P 35/00 20180101; C07D 519/00 20130101;
A61P 43/00 20180101; A61P 9/00 20180101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 519/00 20060101 C07D519/00; A61K 31/551 20060101
A61K031/551; A61K 31/541 20060101 A61K031/541; A61K 45/06 20060101
A61K045/06; A61K 31/5025 20060101 A61K031/5025; A61K 31/506
20060101 A61K031/506; A61K 31/5377 20060101 A61K031/5377; A61K
31/5383 20060101 A61K031/5383; A61K 31/4985 20060101
A61K031/4985 |
Claims
1) A compound according to Formula I: ##STR00557## wherein R.sup.1a
is H, halo or C.sub.1-4 alkyl; R.sup.1b is: halo, C.sub.1-4 alkyl
(which alkyl is optionally substituted with one or more
independently selected halo), or C.sub.1-4 alkoxy (which alkoxy is
optionally substituted with one or more independently selected
halo); X is --S--, --O--, --N.dbd.CH--, --CH.dbd.N-- or
--CH.dbd.CH--; W is N, or CR.sup.3 when W is N, R.sup.2 is: H,
--CN, halo, C.sub.1-4 alkyl (which alkyl is optionally substituted
with one or more independently selected OH, or CN),
--C(.dbd.O)CH.sub.3, --C(.dbd.O)CF.sub.3, --C(.dbd.O)OCH.sub.3,
--C(.dbd.O)NH.sub.2, --NHC(.dbd.O)CH.sub.3, or when W is CR.sup.3,
one of R.sup.2 or R.sup.3 is: H, --CN, halo, C.sub.1-4 alkyl (which
alkyl is optionally substituted with one or more independently
selected OH, or CN), --C(.dbd.O)CH.sub.3, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, --NHC(.dbd.O)CH.sub.3,
and the other is H, or C.sub.1-4 alkyl; R.sup.4 is C.sub.1-4 alkyl;
R.sup.5 is C.sub.1-4 alkyl optionally substituted with one or more
independently selected CN, OH, halo, or --C(.dbd.O)NH.sub.2; one of
Y and Z is CH and the other is N; R.sup.6 is selected from H,
--CH.sub.3 and halo; Cy is: C.sub.4-10 cycloalkyl, 4-10 membered
mono or bicyclic heterocycloalkyl containing one or more heteratoms
independently selected from O, N, and S, or 4-7 membered
heterocycloalkenyl containing 1 double bond, containing one or more
heteroatoms independently selected from O, N, and S; each R.sup.7
is independently selected from: OH, oxo, halo, and C.sub.1-4 alkyl
(which alkyl is optionally substituted with one or more
independently selected OH, or C.sub.1-4 alkoxy); the subscript a is
0, 1 or 2; R.sup.8 is -(L.sub.1-W.sub.1).sub.m-L.sub.2-G.sub.1,
wherein L.sub.1 is absent, or is --O--, --C(.dbd.O)--, --NR.sup.i,
--NR.sup.hC(.dbd.O)--, or --SO.sub.2; W.sub.1 is C.sub.1-4
alkylene; the subscript m is 0, or 1; L.sub.2 is absent, or is
--O--, --C(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--,
--C(.dbd.O)--C(.dbd.O)--, --C(.dbd.O)--C(.dbd.O)NR.sup.a--,
--NR.sup.b--, --C(.dbd.O)NR.sup.c--, --NR.sup.dC(.dbd.O)--,
--NR.sup.jC(.dbd.O)O--, --SO.sub.2--, --SO.sub.2NR.sup.e-- or
--NR.sup.fSO.sub.2--; G.sub.1 is H, --CN, C.sub.1-4 alkyl (which
alkyl is optionally substituted with one or more independently
selected --CN, OH, halo or phenyl), C.sub.3-7 cycloalkyl (which
cycloalkyl is optionally substituted with --NH.sub.2), 5-6 membered
heterocycloalkenyl containing 1 double bond containing one or more
heteratoms independently selected from O, N, and S, (which
heterocycloalkenyl is optionally substituted with one or more
independently selected R.sup.9 groups), 4-10 membered mono, bi or
spirocyclic heterocycloalkyl containing one or more heteratoms
independently selected from O, N, and S, (which heterocycloalkyl is
optionally substituted with one or more independently selected
R.sup.9 groups), or 5-6 membered heteroaryl containing one or more
heteratoms independently selected from O, N, and S, (which
heteroaryl is optionally substituted with one or more independently
selected R.sup.10 groups), or each R.sup.9 is oxo, or R.sup.10;
each R.sup.10 is: --OH, halo, --CN, C.sub.1-4 alkyl (which alkyl is
optionally substituted with one or more independently selected OH,
halo, or phenyl), C.sub.1-4 alkoxy, C.sub.3-7 cycloalkyl, phenyl,
--SO.sub.2CH.sub.3, --C(.dbd.O)C.sub.1-4 alkoxy,
--C(.dbd.O)C.sub.1-4 alkyl, or --NR.sup.gC(.dbd.O)C.sub.1-4 alkyl;
and each R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f,
R.sup.g, R.sup.h, R.sup.i, and R.sup.j is independently selected
from H, and C.sub.1-4 alkyl; or a pharmaceutically acceptable salt,
or a solvate, or a pharmaceutically acceptable salt of a solvate
thereof; or a biologically active metabolite thereof.
2) A compound or pharmaceutically acceptable salt thereof,
according to claim 1, wherein R.sup.1a is F, Cl, --CH.sub.3 or
--C.sub.2H.sub.5.
3) A compound or pharmaceutically acceptable salt thereof,
according to claim 1, wherein R.sup.1b is F, Cl, --CH.sub.3,
--C.sub.2H.sub.5, --CF.sub.3, --OCH.sub.3, or --OCF.sub.3.
4) A compound or pharmaceutically acceptable salt thereof,
according to claim 1, wherein Cy is oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, or thiomorpholinyl.
5) A compound or pharmaceutically acceptable salt thereof,
according to claim 1, wherein the subscript a is 1 or 2, and
R.sup.7 is OH, oxo, F, Cl, or --CH.sub.3.
6) A compound according to claim 1, wherein the compound is
according to Formula IVa, IVb, IVc or IVd: ##STR00558## wherein Y,
Z, R.sup.6, L.sub.1, W.sub.1, L.sub.2, G.sub.1 and the subscript m
are according to claim 1.
7) A compound according to claim 1, wherein the compound is
according to Formula Va, Vb, Vc, or Vd: ##STR00559## wherein Y, Z,
R.sup.6, W.sub.1, and G.sub.1 are according to claim 1.
8) A compound or pharmaceutically acceptable salt thereof,
according to claim 1, wherein W.sub.1 is --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --C(CH.sub.3)H--,
--CH.sub.2--CH.sub.2--CH.sub.2-- or --CH.sub.2--C(CH.sub.3)H--.
9) A compound or pharmaceutically acceptable salt thereof,
according to claim 1, wherein G.sub.1 is oxetanyl, azetidinyl,
tetrahydropyranyl, pyrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, or thiomorpholinyl, each of which is
substituted with one or two independently selected R.sup.9
groups.
10) A compound or pharmaceutically acceptable salt thereof,
according to claim 9, wherein R.sup.9 is R.sup.10 and R.sup.10 is
selected from OH, F, Cl, and --CN.
11) A compound or pharmaceutically acceptable salt thereof,
according to claim 1, wherein R.sup.6 is H, --CH.sub.3 or F.
12) A compound or pharmaceutically acceptable salt thereof,
according to claim 1, wherein Y is N and Z is CH.
13) A compound or pharmaceutically acceptable salt thereof,
according to claim 1, wherein the compound is selected from:
2-((2-ethyl-6-(piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-
-(4-fluorophenyl)thiazole-5-carbonitrile,
2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)im-
idazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbo-
nitrile,
2-((6-(4-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)piperazin-1-yl-
)-2-ethylimidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiaz-
ole-5-carbonitrile,
2-((6-(4-(2-(azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-ethylimidazo[1,2-
-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylim-
idazo[1,2-a]pyrazin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,
(R)-2-((2-ethyl-6-(4-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperazin-1-
-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-
-carbonitrile,
(S)-2-((2-ethyl-6-(4-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperazin-1-
-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-
-carbonitrile,
2-((2-ethyl-6-(4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)imidazo[1-
,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile-
,
2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyli-
midazo[1,2-a]pyrazin-6-yl)piperazin-1-yl)-N-methylacetamide,
2-((2-ethyl-6-(4-(2-morpholino-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]py-
razin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
2-((2-ethyl-6-(4-(2-(3-fluoroazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imi-
dazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbon-
itrile,
2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)acetoyl)piperazin-1-yl-
)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-ca-
rbonitrile,
1-(azetidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methy-
l)amino)imidazo[1,2-a]pyrazin-6-yl)piperazin-1-yl)ethanone,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-a]pyrazin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,
2-(2-((2-ethyl-6-(piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino-
)thiazol-4-yl)-5-fluorobenzonitrile,
2-(2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl-
)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitri-
le,
2-(6-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-
-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)pyridin-2-yl)-5-fluorobenzoni-
trile,
2-(2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazi-
n-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)pyrimidin-4-yl)-5-fluorobe-
nzonitrile,
2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)im-
idazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)pyrimidine-5-car-
bonitrile,
2-((2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-y-
l)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-c-
arbonitrile,
2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-1,2,3,6-tetrahyd-
ropyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl-
)thiazole-5-carbonitrile,
2-((2-ethyl-6-(piperidin-4-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-
-(4-fluorophenyl)thiazole-5-carbonitrile,
2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)im-
idazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbo-
nitrile,
(R)-2-((2-ethyl-6-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)pip-
eridin-4-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)th-
iazole-5-carbonitrile,
(S)-2-((2-ethyl-6-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperidin-4-
-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-
-carbonitrile,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,
2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)im-
idazo[1,2-b]pyridazin-3-yl)(methyl)amino)
-4-(4-fluorophenyl)thiazole-5-carbonitrile,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperazin-1-yl)-1-(2-methylpyrrolidin-1-yl)ethanone,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperazin-1-yl)-1-(2-(hydroxymethyl)pyrrolidin-1-yl)eth-
anone,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imid-
azo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N-methylacetamide,
1-(3,3-difluoropyrrolidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiaz-
ol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethanone-
,
1-(2,5-dimethylpyrrolidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thia-
zol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethanon-
e,
(R)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imid-
azo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethan-
one,
(S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)im-
idazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)eth-
anone,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imid-
azo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N-(2-hydroxyethyl)acetamide,
1-(azetidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methy-
l)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethanone,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperazin-1-yl)-N-isopropyl-N-methylacetamide,
N-(2-ethyl-6-(4-(oxetan-3-yl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-
-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
N-(2-ethyl-6-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)imidazo[1,2-b]py-
ridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
5-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl)piperazin-1-yl)methyl)oxazolidin-2-one,
5-((4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(meth-
yl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)methyl)oxazolidin-2-o-
ne,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo-
[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methy-
l)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide-
,
2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyli-
midazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(2,2,2-trifluoroacetoyl)thiazol-2--
yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N,N-dimethyl-
acetamide,
1-(2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)ami-
no)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethyl)pyrrolidin-2-one,
(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone,
N-(2-ethyl-6-(4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)imidazo[1,2--
b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperazin-1-yl)propan-1-ol,
3-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methy-
l)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)propan-1-ol,
3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperazin-1-yl)propanenitrile,
3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperazin-1-yl)propanamide,
N-(2-ethyl-6-(4-(2-methoxyethyl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3--
yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperazin-1-yl)-N-isopropylacetamide,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone,
tert-butyl
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperazin-1-yl)ethylcarbamate,
N-(2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo-
[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethyl)acetamide, ethyl
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperazin-1-yl)ethylcarbamate, (S)-tert-butyl
4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate,
(S)-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[-
1,2-b]pyridazin-6-yl)piperazin-2-yl)methanol,
(S)-7-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one,
(S)--N-(2-ethyl-6-(3-(methoxymethyl)-4-(methylsulfonyl)piperazin-1-yl)imi-
dazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
(S)-(1-(3-(dimethylamino)propylsulfonyl)-4-(2-ethyl-3-((4-(4-fluorophenyl-
)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-2-yl)me-
thanol,
(S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino-
)imidazo[1,2-b]pyridazin-6-yl)-2-(hydroxymethyl)piperazin-1-yl)-1-(pyrroli-
din-1-yl)ethanone,
(S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidaz-
o[1,2-b]pyridazin-6-yl)-2-(hydroxymethyl)piperazin-1-yl)-1-morpholinoethan-
one,
(S)-8-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imida-
zo[1,2-b]pyridazin-6-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(1H)-one,
(S)-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[-
1,2-b]pyridazin-6-yl)-1-(methylsulfonyl)piperazin-2-yl)methanol,
(S)-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(met-
hyl)amino)imidazo[1,2-b]pyridazin-6-yl)-1-(methylsulfonyl)piperazin-2-yl)m-
ethanol,
(R)-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-
imidazo[1,2-b]pyridazin-6-yl)-1-(methylsulfonyl)piperazin-2-yl)methanol,
3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperazin-1-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one,
N-(2-ethyl-6-(4-(ethylsulfonyl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-y-
l)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)-1-(methylsulfonyl)piperazin-2-yl)ethanol,
2-(4-(2-ethyl-3-((4-(4-fluoro-2-methylphenyl)thiazol-2-yl)(methyl)amino)i-
midazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,
tert-butyl-(1R,4S)-5-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)-
amino)imidazo[1,2-b]pyridazin-6-yl)-2,5-diazabicyclo[2.2.1]heptane
-2-carboxylate,
1-((1R,4S)-5-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)im-
idazo[1,2-b]pyridazin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethanone,
N-(2-ethyl-6-((1S,4R)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2--
yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amin-
e,
N-(2-ethyl-6-(3-azaspiro[5.5]undecan-3-yl)imidazo[1,2-b]pyridazin-3-yl)-
-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
N-(2-ethyl-6-morpholinoimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-
-methylthiazol-2-amine,
6-(1,1-Dioxo-thiomorpholin-4-yl)-2-ethyl-imidazo[1,2-b]pyridazin-3-yl]-[4-
-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine,
N-(6-(4-(dimethylamino)piperidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-y-
l)-4-(4-fluorophenyl)-N-methylthiazol-2-amine, tert-butyl
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)piperidin-4-ylcarbamate,
N-(6-(4-aminopiperidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fl-
uorophenyl)-N-methylthiazol-2-amine,
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperidin-4-yl)methanesulfonamide,
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperidin-4-yl)tetrahydro-2H-pyran-4-carboxamide,
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperidin-4-yl)-2-hydroxyacetamide,
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperidin-4-yl)-3-methyloxetane-3-carboxamide,
tert-butyl
4-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperidin-4-ylcarbamoyl)piperidine-1-carboxylate,
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperidin-4-yl)piperidine-4-carboxamide,
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperidin-4-yl)pyrrolidine-1-carboxamide,
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)piperidin-4-ol,
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)piperidin-3-ol,
N-ethyl-2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)im-
idazo[1,2-b]pyridazin-6-yl)piperidin-3-yloxy)acetamide,
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)piperidin-4-yl)methanol,
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)piperidin-3-yl)methanol,
1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,-
2-b]pyridazin-6-yl)-piperidine-4-carboxylic acid ethyl ester,
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)piperidine-4-carboxylic acid,
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)-N-(2-hydroxyethyl)piperidine-4-carboxamide,
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)piperidine-4-carboxamide,
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)piperidine-3-carboxamide,
[1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1-
,2-b]pyridazin-6-yl)-piperidin-3-ylmethyl]-carbamic acid tert-butyl
ester,
N-(6-(3-(aminomethyl)piperidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-
-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
N-((1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl)piperidin-3-yl)methyl)methanesulfonamide,
[1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1-
,2-b]pyridazin-6-yl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl
ester,
N-(6-(4-(aminomethyl)piperidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-
-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
N-((1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl)piperidin-4-yl)methyl)methanesulfonamide,
3-((1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl)piperidin-4-yl)methyl)-1,1-dimethylurea,
N-((1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl)piperidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamid-
e,
2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[-
1,2-b]pyridazin-6-yl)piperidin-4-yl)-N,N-dimethylacetamide,
N-(2-ethyl-6-(4-morpholinopiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4--
(4-fluorophenyl)-N-methylthiazol-2-amine,
N-(2-ethyl-6-(3-morpholinopiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4--
(4-fluorophenyl)-N-methylthiazol-2-amine,
N-(6-(1,4'-bipiperidin-1'-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-f-
luorophenyl)-N-methylthiazol-2-amine,
1'-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)-1,3'-bipiperidin-4-ol,
N-(2-ethyl-6-(4-phenylpiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-f-
luorophenyl)-N-methylthiazol-2-amine,
N-cyclopropyl-1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino-
)imidazo[1,2-b]pyridazin-6-yl)piperidine-4-sulfonamide,
1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)-1,4-diazepan-1-yl)ethanone,
N-(2-ethyl-6-(4-(methylsulfonyl)-1,4-diazepan-1-yl)imidazo[1,2-b]pyridazi-
n-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
N-(2-ethyl-6-(8-oxa-2-azaspiro[4.5]decan-2-yl)imidazo[1,2-b]pyridazin-3-y-
l)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
7-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)-1-oxa-3,7-diazaspiro[4.4]nonan-2-one,
7-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)-3-methyl-1-oxa-3,7-diazaspiro[4.4]nonan-2-one,
7-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)a-
mino)imidazo[1,2-b]pyridazin-6-yl)-3-methyl-1-oxa-3,7-diazaspiro[4.4]nonan-
-2-one,
7-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidaz-
o[1,2-b]pyridazin-6-yl)-2,7-diazaspiro[4.4]nonane-1,3-dione,
tert-butyl
5-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate,
N-(2-ethyl-6-(5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)im-
idazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
1-(5-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethanone,
N-(6-(5-(3-chloropropylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-
-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-a-
mine,
N-(6-(5-(3-(dimethylamino)propylsulfonyl)hexahydropyrrolo[3,4-c]pyrr-
ol-2(1H)-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-met-
hylthiazol-2-amine,
N-(2-ethyl-6-(5-(3-morpholinopropylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-
-2(1H)-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-
-2-amine,
(S)-1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-
imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-3-carbonitrile,
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)pyrrolidin-3-ol,
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)pyrrolidin-3-yl formate,
N-(2-ethyl-6-(3-thiomorpholinopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-y-
l)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
1-(3-((5-chloro-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimid-
azo[1,2-b]pyridazin-6-yl)pyrrolidin-3-one, tert-butyl
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)pyrrolidin-3-ylcarbamate,
N-(6-(3-aminopyrrolidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-f-
luorophenyl)-N-methylthiazol-2-amine, methyl
2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)pyrrolidin-3-ylamino)acetate,
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)pyrrolidin-3-yl)-2-hydroxyacetamide,
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)pyrrolidin-3-yl)methanesulfonamide,
(S)-1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl)pyrrolidine-2-carboxylic acid,
1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,-
2-b]pyridazin-6-yl)-pyrrolidine-3-carboxylic acid methyl ester,
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)-N-(2-hydroxyethyl)pyrrolidine-3-carboxamide,
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)pyrrolidin-3-yl)(morpholino)methanone,
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)pyrrolidin-2-yl)methanol,
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)pyrrolidin-3-yl)methanol,
(1-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)-
amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)methanol,
3-(4-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo-
[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)piperazin-1-yl)propan-1-ol,
4-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)pyrrolidin-3-yl)piperazin-2-one,
N-(2-ethyl-6-(3-morpholinopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-
-(4-fluorophenyl)-N-methylthiazol-2-amine,
(2-((2-ethyl-6-(3-morpholinopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-
(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)methanol,
2-((2-ethyl-6-(3-morpholinopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(-
methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
{6-[3-(1,1-Dioxo-thiomorpholin-4-yl)-pyrrolidin-1-yl]-2-ethyl-imidazo[1,2-
-b]pyridazin-3-yl}-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine,
N-(2-ethyl-6-(3-(piperidin-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-
-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
1-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)pyrrolidin-3-yl)piperidin-4-ol,
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)azetidin-3-yl)methanol,
[1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1-
,2-b]pyridazin-6-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester,
2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)azetidin-3-ylamino)-1-(3-hydroxyazetidin-1-yl)ethanone,
2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)azetidin-3-ylamino)-N,N-dimethylacetamide,
2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)azetidin-3-ylamino)-N-methylacetamide,
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)azetidin-3-yl)methanesulfonamide,
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)azetidin-3-yl)(3-hydroxypyrrolidin-1-yl)methanone,
2-((2-ethyl-6-(4-((2-oxooxazolidin-5-yl)methyl)piperazin-1-yl)imidazo[1,2-
-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile-
,
(S)-2-((2-ethyl-6-(3-(hydroxymethyl)-4-(methylsulfonyl)piperazin-1-yl)im-
idazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-car-
bonitrile,
2-((2-ethyl-6-(2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-7-yl)imidaz-
o[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carboni-
trile,
2-((2-ethyl-6-(3-methyl-2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-7-yl)i-
midazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-ca-
rbonitrile,
2-((2-ethyl-6-(3-methyl-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonan-7-yl)imidazo-
[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonit-
rile, tert-butyl
7-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimida-
zo[1,2-b]pyridazin-6-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate,
2-((2-ethyl-6-(2,7-diazaspiro[4.4]nonan-2-yl)imidazo[1,2-b]pyridazin-3-yl-
)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
2-((6-(7-acetoyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-ethylimidazo[1,2-b]pyri-
dazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
methyl
(1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-et-
hylimidazo[1,2-b]pyridazin-6-yl)-3-hydroxypyrrolidin-3-yl),
N-((1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyli-
midazo[1,2-b]pyridazin-6-yl)-3-hydroxypyrrolidin-3-yl)methyl)acetamide,
N-((1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyli-
midazo[1,2-b]pyridazin-6-yl)-3-hydroxypyrrolidin-3-yl)methyl)isobutyramide-
,
2-((2-ethyl-6-(3-hydroxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(me-
thyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
2-((2-ethyl-6-(3-oxopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)-
amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
2-((2-ethyl-6-(3-(hydroxymethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-
-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
(S)-2-((2-ethyl-6-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethylamino)pyrrolid-
in-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thia-
zole-5-carbonitrile,
(S)-2-(1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-eth-
ylimidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylamino)-N,N-dimethylacetamide-
,
(R)-2-((2-ethyl-6-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethylamino)pyrroli-
din-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thi-
azole-5-carbonitrile,
(R)-2-(1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-eth-
ylimidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylamino)-N,N-dimethylacetamide-
,
2-((6-(3-((2S,6R)-2,6-dimethylmorpholino)pyrrolidin-1-yl)-2-ethylimidazo-
[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonit-
rile,
2-((2-ethyl-6-(3-(4-(hydroxymethyl)piperidin-1-yl)pyrrolidin-1-yl)im-
idazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-car-
bonitrile,
2-((6-(3-(4-acetoylpiperazin-1-yl)pyrrolidin-1-yl)-2-ethylimida-
zo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbon-
itrile,
N-(1-(1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-
-2-ethylimidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)piperidin-4-yl)-N-met-
hylacetamide,
2-((2-ethyl-6-(3-(4-hydroxypiperidin-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]p-
yridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
2-((2-ethyl-6-(3-(4-methoxypiperidin-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]p-
yridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
2-((2-ethyl-6-((3S,4S)-3-hydroxy-4-morpholinopyrrolidin-1-yl)imidazo[1,2--
b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
1-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)a-
mino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ol,
(2-((2-ethyl-6-(8-oxa-2-azaspiro[4.5]decan-2-yl)imidazo[1,2-b]pyridazin-3-
-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)methanol,
[1-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-i-
midazo[1,2-b]pyridazin-6-yl)-azetidin-3-yl]-carbamic acid
tert-butyl ester,
2-((6-(3-aminoazetidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)(-
methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
2-((2-ethyl-6-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethylamino)azetidin-1-y-
l)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-
-carbonitrile,
N-(1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylim-
idazo[1,2-b]pyridazin-6-yl)azetidin-3-yl)methanesulfonamide,
2-((2-ethyl-6-(3-(morpholine-4-carbonyl)azetidin-1-yl)imidazo[1,2-b]pyrid-
azin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
2-((2-ethyl-6-(3-(3-hydroxypyrrolidine-1-carbonyl)azetidin-1-yl)imidazo[1-
,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitri-
le,
4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo-
[1,2-b]pyridazin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid
tert-butyl ester,
N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1-
,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)--
1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)methanol,
2-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl-
)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetonitrile-
,
3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfony-
l)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propanamide,
3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl-
)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propanenitrile,
3-(3-((4-(4-fluorophenyl)-5-(2,2,2-trifluoroacetoyl)thiazol-2-yl)(methyl)-
amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)pr-
opanenitrile,
3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl-
)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propan-1-ol,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methy-
l)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide-
,
2-(2-((2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imid-
azo[1,2-b]pyridazin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,
2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazi-
n-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,
2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazi-
n-3-yl)(methyl)amino)-5-(hydroxymethyl)thiazol-4-yl)-5-fluorobenzonitrile,
2-(2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl-
)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonit-
rile,
2-(4-(3-((4-(2-cyano-4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-et-
hylimidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,
2-(4-(3-((4-(2-cyano-4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylim-
idazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N-methylacetamide,
2-(2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl-
)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-5-methylthiazol-4-yl)-5-fluor-
obenzonitrile,
2-(4-(3-((4-(2-cyano-4-fluorophenyl)-5-methylthiazol-2-yl)(methyl)amino)--
2-ethylimidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N-methylacetamide,
2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)im-
idazo[1,2-b]pyridazin -3-yl)(methyl)amino)
-4-(4-fluorophenyl)thiazole-5-carbonitrile,
2-(6-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl-
)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)pyridin-2-yl)-5-fluorobenzonit-
rile,
2-(4-(2-ethyl-3-((6-(4-fluorophenyl)pyridin-2-yl)(methyl)amino)imida-
zo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone-
,
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)pyrimidin-2-yl)(methyl)amino)imidazo-
[1,2-b]pyridazin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,
2-(4-(2-ethyl-3-((2-(4-fluorophenyl)pyrimidin-4-yl)(methyl)amino)imidazo[-
1,2-b]pyridazin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,
2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)im-
idazo[1,2-b]pyridazin-3-yl)(methyl)amino)-6-(4-fluorophenyl)nicotinonitril-
e,
6-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)-
imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-2-(4-fluorophenyl)nicotinonitr-
ile,
2-(5-((2-ethyl-6-(piperidin-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl-
)amino)-1,2,4-thiadiazol-3-yl)-5-fluorobenzonitrile, and
2-(5-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl-
)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-1,2,4-thiadiazol-3-yl)-5-fluo-
robenzonitrile.
14) A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a pharmaceutically effective amount of a
compound according to claim 1.
15) A pharmaceutical composition according to claim 14, comprising
a further therapeutic agent.
16) A compound or pharmaceutically acceptable salt thereof,
according to claim 1, for use in medicine.
17) A compound or pharmaceutically acceptable salt thereof,
according to claim 1, for use in the treatment of fibrotic
diseases, proliferative diseases, inflammatory diseases, autoimmune
diseases, respiratory diseases, cardiovascular diseases,
neurodegenerative diseases, dermatological disorders, and/or
abnormal angiogenesis associated diseases.
18) The use of a compound or pharmaceutically acceptable salt
thereof according to claim 1, wherein said compound is administered
in combination with a further therapeutic agent.
19) A method for the treatment, or prevention of diseases or
conditions selected from fibrotic diseases, proliferative diseases,
inflammatory diseases, autoimmune diseases, respiratory diseases,
cardiovascular diseases, neurodegenerative diseases, dermatological
disorders, and/or abnormal angiogenesis associated diseases,
comprising administering an amount of compound according to claim
1, sufficient to effect said treatment, or prevention.
20) The method according to claim 19, wherein the compound, or the
pharmaceutical composition, is administered in combination with a
further therapeutic agent.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 14/898,327, filed on Dec. 14, 2015,
which is a national stage filing under section 371 of International
Application No. PCT/EP2014/062241, filed on Jun. 12, 2014, and
published in English on Dec. 24, 2014 as WO 2014/202458 A1, which
claims priority to U.S. Provisional Application No. 61/836,831
filed on Jun. 19, 2013. The entire contents of each of said earlier
applications are hereby incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds that are
inhibitors of autotaxin, also known as ectonucleotide
pyrophosphatase/phosphodiesterase 2 (NPP2 or ENPP2), that is
involved in fibrotic diseases, proliferative diseases, inflammatory
diseases, autoimmune diseases, respiratory diseases, cardiovascular
diseases, neurodegenerative diseases, dermatological disorders,
and/or abnormal angiogenesis associated diseases. The present
invention also provides methods for the production of a compound of
the invention, pharmaceutical compositions comprising a compound of
the invention, methods for the prophylaxis and/or treatment of
diseases involving fibrotic diseases, proliferative diseases,
inflammatory diseases, autoimmune diseases, respiratory diseases,
cardiovascular diseases, neurodegenerative diseases, dermatological
disorders, and/or abnormal angiogenesis associated diseases by
administering a compound of the invention.
BACKGROUND OF THE INVENTION
[0003] Autotaxin (ATX; also known as ENPP2 (ectonucleotide
pyrophosphatase/phosphodiesterase 2) or lysophospholipase D) is a
.about.120 kDa protein that belongs to the ENPP family of enzymes
which is composed of seven members, out of which ENPP1 and ENPP3
are the closest to ATX. Whereas ENPP1 and ENPP3 are active in
converting ATP into pyrophosphate (a regulator of mineralization
and calcification processes in bone), ATX is the only ENPP enzyme
with lysophospholipase D (lysoPLD) activity and is responsible for
the hydrolysis of lysophosphatidylcholine (LPC) to produce the
bioactive lipid lysophosphatidic acid (LPA). Several pieces of
evidence have established ATX as the main source of LPA in blood.
For example, blood LPA and ATX levels have been shown to be
strongly correlated in humans. In addition, LPA levels are reduced
by 50% in mice carrying a heterozygous null mutation of ATX (Tanaka
et al. 2006).
[0004] Due to the importance of LPA as a biological mediator, the
levels of bio-active LPA are expected to be strictly spatially and
temporally controlled. The relatively short half life of
circulating LPA (.about.3 min) in mice is in line with this
expectation. In the circulation, where LPC levels are very high
(100-200 .mu.M, mainly albumin-bound), ATX is constitutively active
but newly produced LPA is rapidly degraded by membrane-bound
phosphatases and levels of plasma LPA are thereby kept low (in the
low .mu.m range). This is confirmed by the fact that in cell-free
plasma ex vivo, LPA levels increase at a steady rate. In addition,
LPA in blood is bound to serum albumin, which might further reduce
the levels of bio-active LPA. Besides this first level of control
of LPA levels, the spatial control of LPA production is ensured by
the capacity of ATX to bind to cell surface molecules such as
integrins and heparan sulphate proteoglycans (HSPs) to facilitate
LPA release near to its cognate receptors. Several pieces of
evidence support this hypothesis. First, the structural studies of
ATX are supporting the fact that the ATX structure is compatible
with such a process (Hausmann et al. 2011). In addition, several
reports indicated how ATX is involved in lymphocyte homing through
the interaction with cell surface integrins (Kanda et al. 2008). It
was shown, for example, that ATX can be induced on high endothelial
venules (HEVs) on sites of inflammation. This ATX expressed by HEVs
acts on HEVs in situ to facilitate lymphocyte binding to
endothelial cells (Nakasaki et al. 2008). As such, ATX not only
drives the formation of LPA but, through these cellular
interactions, also ensures specificity in LPA signaling.
[0005] ATX is widely expressed, with highest mRNA levels detected
in brain, lymph nodes, kidney, and testis. Originally discovered as
`autocrine motility factor` in melanoma cells, ATX has emerged as
the key LPA-producing enzyme in plasma and tissues. Unfortunately,
embryonic lethality has hampered studies of the importance of ATX
in adult life. This embryonic lethality reflects the key role of
LPA in various developmental processes, vasculogenesis in
particular. Knock-out studies of the LPA receptors have been more
informative in terms of unraveling the physiological role of LPA.
LPA acts through at least six distinct (G protein)-coupled
receptors (LPA1-6) found on the surface of different cell types,
three of which belong to the edg receptor family and three to the
non-edg receptor family. LPA interacts with specific G
protein-coupled receptors (GPCRs), namely LPA1 (also known as
EDG2), LPA2 (also known as EDG4), LPA3 (also known as EDG7), LPA4
(also known as GPR23/p2y9), LPA5 (also known as GPR92/93), LPA6
(also known as p2y5). LPA has also been described to interact with
three other GPCRs (GPR87, p2y10, GPR35). In addition, a preference
of LPA receptors for specific LPA species has been demonstrated
(Bandoh et al. 2000). As such, the specificity of the LPA
activities is controlled by the expression pattern of the LPA
receptors and their downstream signaling route.
[0006] The main part of the LPA responses are mediated through
trimeric G-proteins and include but are not limited to
mitogen-activated protein kinase (MAPK) activation, adenylyl
cyclase (AC) inhibition/activation, phospholipase C (PLC)
activation/Ca.sup.2+ mobilization, arachidonic acid release,
Akt/PKB activation, and the activation of small GTPases, Rho, ROCK,
Rac, and Ras. Other pathways that are affected by LPA receptor
activation include cell division cycle 42/GTP-binding protein
(Cdc42), proto-oncogene serine/threonine-protein kinase Raf
(c-RAF), proto-oncogene tyrosine-protein kinase Src (c-src),
extracellular signal-regulated kinase (ERK), focal adhesion kinase
(FAK), guanine nucleotide exchange factor (GEF), glycogen synthase
kinase 3b (GSK3b), c-jun amino-terminal kinase (JNK), MEK, myosin
light chain II (MLC II), nuclear factor kB (NF-kB),
N-methyl-D-aspartate (NMDA) receptor activation,
phosphatidylinositol3-kinase (PI3K), protein kinase A (PKA),
protein kinase C (PKC), and ras-related C3 botulinum toxin
substrate 1 (RAC1). The actual pathway is influenced by cell type,
expression level of a receptor or signaling protein, receptor
usage, and LPA concentration (Tania et al. 2010). LPA has a broad
range of physiological actions and various cellular effects (for
example blood pressure regulation, platelet activation, smooth
muscle contraction, cell growth, cell rounding, neurite retraction,
actin stress fiber formation and cell migration). In addition, a
preference of LPA receptors for specific LPA species has been
demonstrated (Bandoh et al. 2000). The knock-out studies for these
receptors indicated a role in bone development (Gennero et al.
2011), and neurogenesis (Matas-Rico et al. 2008), embryo
implantation (Ye et al. 2005) and the formation of blood and
lymphatic vessels (Sumida et al. 2010).
[0007] With regard to pathophysiology, a role for LPA and LPA
receptors has been claimed in various patho-physiological
conditions such as proliferative diseases, neuropathic pain,
inflammation, autoimmune diseases, fibrosis, lymphocyte tracking in
lymph nodes, obesity, diabetes, or embryonic blood vessel
formation.
[0008] The role of LPA in lung fibrosis has been well described in
literature and also an involvement in asthma has been claimed. The
present inventors however are the first to report a link to chronic
obstructive pulmonary disease COPD.
[0009] Several lines of evidence suggest a role for ATX in the
control of lung function in disease through effects on lung
epithelial cells, fibroblasts and smooth muscle cells. In general,
inflammatory conditions in the lung are often described as
associated with increased ATX and LPA levels. Instillation of LPS
in mice, for example, induces increased ATX and LPA levels in the
broncho-alveolar lavage (BAL) fluid (J. Zhao et al. 2011). Also in
humans, a segmental LPS challenge led to increased LPA levels
(Georas et al. 2007). Overall, the role of LPA in activating lung
epithelial cells, the first line of defense to inhaled noxious
stimuli, towards increased cytokine and chemokine production and
migration have been extensively described (Y. Zhao and Natarajan
2013). Exogenous LPA promotes inflammatory responses by regulating
the expression of chemokines, cytokines, and cytokine receptors in
lung epithelial cells. In addition to the modulation of
inflammatory responses, LPA regulates cytoskeleton rearrangement
and confers protection against lung injury by enhancing lung
epithelial cell barrier integrity and remodeling.
[0010] In the asthmatic individual, the release of normal repair
mediators, including LPA, is exaggerated or the actions of the
repair mediators are inappropriately prolonged leading to
inappropriate airway remodeling. Major structural features of the
remodeled airway observed in asthma include a thickened lamina
reticularis (the basement membrane-like structure just beneath the
airway epithelial cells), increased numbers and activation of
myofibroblasts, thickening of the smooth muscle layer, increased
numbers of mucus glands and mucus secretions, and alterations in
the connective tissue and capillary bed throughout the airway wall.
ATX and/or LPA may contribute to these structural changes in the
airway, for example ATX and/or LPA are involved in acute airway
hyperresponsiveness in asthma. The lumen of the remodeled asthmatic
airway is narrower due to the thickening of the airway wall, thus
decreasing airflow. Additionally, LPA contributes to the long-term
structural remodeling and the acute hyperresponsiveness of the
asthmatic airway, for example LPA contributes to the
hyper-responsiveness that is a primary feature of acute
exacerbations of asthma. Reports describing the role of LPA in
asthma generated different conclusions, ranging from a protective
role (Y. Zhao et al. 2009) to a negative role (Emo et al. 2012).
The testing of autotaxin inhibitors in models for airway diseases
as described herein allows for the clarification of the potential
of this enzyme as a drug target.
[0011] Fibroblast proliferation and contraction and extracellular
matrix secretion stimulated by LPA contributes to the
fibroproliferative features of other airway diseases, such as the
peribronchiolar fibrosis present in chronic bronchitis, and
interstitial lung diseases and severe asthma. LPA plays a role in
the fibrotic interstitial lung diseases and obliterative
bronchiolitis, where both collagen and myofibroblasts are
increased. Studies related to IPF (idiopathic pulmonary fibrosis)
indicated an increase in LPA levels in the BAL fluid of patients
(Tager et al. 2008). Further LPA1 knock-out and inhibitor studies
revealed a key role for LPA in fibrotic processes in lung and were
complemented by studies using cell-specific knock-out mice lacking
ATX in bronchial epithelial cells and macrophages. These mice were
shown to be less sensitive to models of lung fibrosis (Oikonomou et
al. 2012). A role for LPA in other fibrotic diseases (kidney and
skin) was based on similar types of observations (Pradere et al.
2007), (Castelino et al. 2011). The role of LPA in lung remodeling
relates to the effects of LPA on both lung fibroblasts (through
LPA1) and epithelial cells (through LPA2) (M. Y. Xu et al. 2009)
have demonstrated that LPA2 plays a key role in the activation of
TGF.beta. in epithelial cells under fibrotic conditions. The role
of LPA in remodeling and fibrosis is relevant to COPD, IPF and
asthma, diseases in which lung remodeling as a long term outcome
will limit lung function. Finally, of interest towards lung
diseases, in mice, ATX is one of the three main QTLs that appear to
be associated with differences in lung function (Ganguly et al.
2007).
[0012] One prominent area of research interest is the role of
ATX-LPA signaling in cancer (Braddock 2010). Although
cancer-specific mutations in ATX have not been identified so far,
overexpression of ATX or individual LPA receptors in xenografted
and transgenic mice promotes tumour formation, angiogenesis and
metastasis. Conversely, ATX knockdown in mammary carcinoma cells
reduces their metastatic spread to bone. Several human cancers show
elevated ATX and/or aberrant LPA receptor expression patterns, as
revealed by microarray analyses. Autotaxin is viewed as a
pro-metastatic enzyme. It has initially been isolated from the
conditioned medium of human melanoma cells that stimulates a myriad
of biological activities, including angiogenesis and the promotion
of cell growth, migration, survival, and differentiation through
the production of LPA (M.-E. Lin, Herr, and Chun 2010). LPA
contributes to tumorigenesis by increasing motility and
invasiveness of cells. The initiation, progression and metastasis
of cancer involve several concurrent and sequential processes
including cell proliferation and growth, survival and
anti-apoptosis, migration of cells, penetration of foreign cells
into defined tissues and/or organs, and promotion of
angiogenesis.
[0013] Therefore, the control of each of these processes by LPA
signaling in physiological and pathophysiological conditions
underscores the potential therapeutic usefulness of modulating LPA
signaling pathways for the treatment of cancer. In particular, LPA
has been implicated in the initiation or progression of ovarian
cancer, prostate cancer, breast cancer, melanoma, head and neck
cancer, bowel cancer (colorectal cancer), thyroid cancer,
glioblastoma, follicular lymphoma and other cancers (Gardell,
Dubin, and Chun 2006; Murph et al. 2008; Kishi et al. 2006).
[0014] Furthermore, autotaxin is implicated in the invasive and
metastatic process of tumor cells, since ectopic overexpression of
autotaxin is frequently observed in malignant tumor tissues such as
ovarian cancer (Vidot et al. 2010), breast cancer (Panupinthu, Lee,
and Mills 2010; Zhang et al. 2009), prostate cancer (Nouh et al.
2009), renal cancer, Hodgkin lymphoma (Baumforth et al. 2005),
hepatocellular carcinoma (Wu et al. 2010), lung cancer (X. Xu and
Prestwich 2010), and glioblastoma (Kishi et al. 2006). Autotaxin
overexpression has also been found in a variety of tumors such as
malignant melanoma, teratocarcinoma, neuroblastoma, non-small-cell
lung cancer, renal cell carcinoma (Stassar et al. 2001).
[0015] Furthermore, expression of autotaxin by cancer cells
controls osteolytic bone metastasis formation. In particular, LPA
stimulates directly cancer growth and metastasis, and osteoclast
differentiation. Therefore, targeting the autotaxin/LPA signaling
route has also been found to be beneficial in patients with bone
metastases (David et al. 2010). Finally, the inhibition of
autotaxin seems to provide a beneficial adjuvant to chemotherapy
for preventing tumor growth and metastasis in patients with high
autotaxin expression in their tumors (Gaetano et al. 2009).
[0016] Upregulation of the autotaxin-LPA signaling pathway has been
observed in a variety of inflammatory conditions. For example,
pro-inflammatory effects of LPA include degranulation of mast
cells, contraction of smooth-muscle cells and release of cytokines
from dendritic cells. As an indication for its general role in
inflammation, LPA and autotaxin activity have been shown to be
induced by carageenan injection into the mouse air pouch model,
which is used to develop anti-inflammatory drugs, including
cyclooxygenase inhibitors for arthritis. Furthermore, a reduction
in plasma and air pouch LPA has been observed in this rat air pouch
model using an autotaxin inhibitor, confirming the role of
autotaxin during inflammation as a major source of LPA (Gierse et
al. 2010). It has been observed that autotaxin inhibitors reduce
LPA and PGE2 and also reduce inflammatory pain.
[0017] As another general role in inflammatory diseases, LPA has
been shown to induce chemokinesis in T-cells. Intravenous injection
of enzymatically inactive autotaxin has been shown to attenuate the
homing of T-cells to lymphoid tissues, likely by competing with
endogenous autotaxin and exerting a dominant-negative effect. In
certain instances, autotaxin facilitates lymphocyte entry into
lymphoid organs (Kanda et al. 2008). Therefore an autotaxin
inhibitor may block lymphocyte migration into secondary lymphoid
organs and be of benefit in autoimmune diseases.
[0018] Specifically in rheumatoid arthritis, an increased
expression of ATX in synovial fibroblasts from RA patients was
demonstrated and ablation of ATX expression in mesenchymal cells
(including synovial fibroblasts) resulted in attenuated symptoms in
mouse models for rheumatoid arthritis (Nikitopoulou et al. 2012).
As such, the role of autotaxin in rheumatoid arthritis has been
strongly established.
[0019] Several lines of evidence suggest a role for LPA in vascular
injury and atherosclerosis. These relate to the role of LPA in
modulating endothelial barrier function and the phenotype of
vascular smooth muscle cells and the action of LPA as a weak
platelet agonist. Platelets have been identified as important
participants in LPA production in the circulation in some settings,
mainly by providing sufficient LPC amounts. Plasma autotaxin
associates with platelets during aggregation and concentrates in
arterial thrombus, and activated but not resting platelets bind
recombinant autotaxin in an integrin-dependent manner. Experimental
induction of thrombocytopenia in rats, using an anti-platelet
antibody, decreases the production of LPA in serum by almost 50%,
which suggests a role for LPA during clotting. In some instances,
transgenic overexpression of autotaxin elevates circulating LPA
levels and induces a bleeding diathesis and attenuation of
thrombosis in mice. Intravascular administration of exogenous LPA
recapitulates the prolonged bleeding time observed in autotaxin-Tg
mice. Finally, autotaxin +/- mice, which have .about.50% normal
plasma LPA levels, are more prone to thrombosis.
[0020] In addition to a role in blood clotting, LPA has multiple
effects on the endothelial monolayer permeability increase, and
endothelial cells, in particular in critical aspects of
angiogenesis such as cell migration stimulation and invasion.
Furthermore, LPA also exerts migratory and contractile effects on
vascular smooth muscle cells: autotaxin-mediated LPA production and
subsequent LPA signaling contributes to vascular development by
stimulating endothelial cell migration and invasion as well as
regulating adhesive interactions with the extracellular matrix and
smooth muscle cells. For example, similar vascular defects have
been observed in autotaxin-deficient mice and in mice lacking genes
involved in cell migration and adhesion (van Meeteren et al. 2006).
Therefore an autotaxin inhibitor may have benefit in some diseases
involving dysregulated angiogenesis.
[0021] LPA induces neuropathic pain as well as demyelination and
pain-related protein expression changes via LPA1 (Inoue et al.
2008). ATX heterozygous knockout mice show about 50% recovery of
nerve injury-induced neuropathic pain compared to wild type mice.
Lysophosphatidylcholine (LPC), also known as lyso-lecithin, is
known to induce neuropathic pain. It has been observed that
LPC-induced neuropathic pain is partially reduced in ATX
heterozygous knockout mice. These results support the idea that LPA
is produced by autotaxin resulting in neuropathic pain (M.-E. Lin,
Herr, and Chun 2010).
[0022] Autotaxin is also implicated in metabolic diseases, in
particular obesity and diabetes (Federico et al. 2012). In some
instances, autotaxin is responsible for the lysoPLD activity
released by adipocytes and exerts a paracrine control on
preadipocyte growth via an LPA-dependent mechanism. In addition,
autotaxin is upregulated during adipocyte differentiation and in
genetic obesity. In certain instances, autotaxin mRNA is
upregulated in adipocytes from db/db mice suggesting that the
upregulation of autotaxin is related to the severe type 2 diabetes
phenotype and adipocyte insuline resistance. In some instances,
upregulation of adipocyte autotaxin is associated with type 2
diabetes in human (Ferry et al. 2003). The relationship between
adipocyte and autotaxin biology suggests the use of an autotaxin
inhibitor for the treatment of metabolic diseases.
[0023] Finally, two other conditions clearly related to autotaxin
biology are cholestatic pruritus (Kremer et al. 2010) and
regulation of ocular pressure (Iyer et al. 2012).
[0024] The current therapies are not satisfactory and therefore
there remains a need to identify further compounds that may be of
use in the treatment of fibrotic diseases, proliferative diseases,
inflammatory diseases, autoimmune diseases, respiratory diseases,
cardiovascular diseases, neurodegenerative diseases, dermatological
disorders, and/or abnormal angiogenesis associated diseases. The
present invention therefore provides compounds, methods for their
manufacture and pharmaceutical compositions comprising a compound
of the invention together with a suitable pharmaceutical carrier.
The present invention also provides for the use of a compound of
the invention in the preparation of a medicament for the treatment
of fibrotic diseases, proliferative diseases, inflammatory
diseases, autoimmune diseases, respiratory diseases, cardiovascular
diseases, neurodegenerative diseases, dermatological disorders,
and/or abnormal angiogenesis associated diseases.
SUMMARY OF THE INVENTION
[0025] The present invention is based on the identification of
novel compounds, and their ability to act as inhibitors of
autotaxin and that they may be useful for the treatment of fibrotic
diseases, proliferative diseases, inflammatory diseases, autoimmune
diseases, respiratory diseases, cardiovascular diseases,
neurodegenerative diseases, dermatological disorders, and/or
abnormal angiogenesis associated diseases. The present invention
also provides methods for the production of these compounds,
pharmaceutical compositions comprising these compounds and methods
for the prophylaxis and/or treatment of fibrotic diseases,
proliferative diseases, inflammatory diseases, autoimmune diseases,
respiratory diseases, cardiovascular diseases, neurodegenerative
diseases, dermatological disorders, and/or abnormal angiogenesis
associated diseases by administering the compounds of the
invention.
[0026] Accordingly, in a first aspect of the invention, the
compounds of the invention are provided having a Formula (I):
##STR00002## [0027] wherein [0028] R.sup.1a is H, halo or C.sub.1-4
alkyl; [0029] R.sup.1b is: [0030] halo, [0031] C.sub.1-4 alkyl
(which alkyl is optionally substituted with one or more
independently selected halo), or [0032] C.sub.1-4 alkoxy (which
alkoxy is optionally substituted with one or more independently
selected halo); [0033] X is --S--, --O--, --N.dbd.CH--,
--CH.dbd.N-- or --CH.dbd.CH--; [0034] W is N, or CR.sup.3 [0035]
when W is N, R.sup.2 is: [0036] H, [0037] --CN, [0038] halo, [0039]
C.sub.1-4 alkyl (which alkyl is optionally substituted with one or
more independently selected OH, or CN), [0040] --C(.dbd.O)CH.sub.3,
[0041] --C(.dbd.O)CF.sub.3, [0042] --C(.dbd.O)OCH.sub.3, [0043]
--C(.dbd.O)NH.sub.2, or [0044] --NHC(.dbd.O)CH.sub.3, or [0045]
when W is CR.sup.3, one of R.sup.2 or R.sup.3 is: [0046] H, [0047]
--CN, [0048] halo, [0049] C.sub.1-4 alkyl (which alkyl is
optionally substituted with one or more independently selected OH,
or CN), [0050] --C(.dbd.O)CH.sub.3, [0051] --C(.dbd.O)CF.sub.3,
[0052] --C(.dbd.O)OCH.sub.3, [0053] --C(.dbd.O)NH.sub.2, [0054]
--NHC(.dbd.O)CH.sub.3, [0055] and the other is H, or C.sub.1-4
alkyl; [0056] R.sup.4 is C.sub.1-4 alkyl; [0057] R.sup.5 is
C.sub.1-4 alkyl optionally substituted with one or more
independently selected CN, OH, halo, or --C(.dbd.O)NH.sub.2; [0058]
one of Y and Z is CH and the other is N; [0059] R.sup.6 is selected
from H, --CH.sub.3 and halo; [0060] Cy is: [0061] C.sub.4-10
cycloalkyl, [0062] 4-10 membered mono or bicyclic heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, or [0063] 4-7 membered heterocycloalkenyl containing 1
double bond, containing one or more heteroatoms independently
selected from O, N, and S; [0064] each R.sup.7 is independently
selected from: [0065] OH, [0066] oxo, [0067] halo, and [0068]
C.sub.1-4 alkyl (which alkyl is optionally substituted with one or
more independently selected OH, or C.sub.1-4 alkoxy); [0069] the
subscript a is 0, 1 or 2; [0070] R.sup.8 is
-(L.sub.1-W.sub.1).sub.m-L.sub.2-G.sub.1, [0071] wherein [0072]
L.sub.1 is absent, or is --O--, --C(.dbd.O)--, --NR.sup.i,
--NR.sup.hC(.dbd.O)--, or --SO.sub.2--; [0073] W.sub.1 is C.sub.1-4
alkylene; [0074] the subscript m is 0, or 1; [0075] L.sub.2 is
absent, or is --O--, --C(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--,
--C(.dbd.O)--C(.dbd.O)--, --C(.dbd.O)--C(.dbd.O)NR.sup.a--, [0076]
--NR.sup.b--, --C(.dbd.O)NR.sup.c--, --NR.sup.dC(.dbd.O)--,
--NR.sup.jC(.dbd.O)O--, --SO.sub.2--, --SO.sub.2NR.sup.e-- or
--NR.sup.fSO.sub.2--; [0077] G.sub.1 is [0078] H, [0079] --CN,
[0080] C.sub.1-4 alkyl (which alkyl is optionally substituted with
one or more independently selected --CN, OH, halo or phenyl),
[0081] C.sub.3-7 cycloalkyl (which cycloalkyl is optionally
substituted with --NH.sub.2), [0082] 5-6 membered
heterocycloalkenyl containing 1 double bond containing one or more
heteroatoms independently selected from O, N, and S, (which
heterocycloalkenyl is optionally substituted with one or more
independently selected R.sup.9 groups), [0083] 4-10 membered mono,
bi or spirocyclic heterocycloalkyl containing one or more
heteroatoms independently selected from O, N, and S, (which
heterocycloalkyl is optionally substituted with one or more
independently selected R.sup.9 groups), or [0084] 5-6 membered
heteroaryl containing one or more heteroatoms independently
selected from O, N, and S, (which heteroaryl is optionally
substituted with one or more independently selected R.sup.10
groups), or [0085] each R.sup.9 is oxo, or R.sup.10; [0086] each
R.sup.10 is: [0087] --OH, [0088] halo, [0089] --CN, [0090]
C.sub.1-4 alkyl (which alkyl is optionally substituted with one or
more independently selected OH, halo, or phenyl), [0091] C.sub.1-4
alkoxy, [0092] C.sub.3-7 cycloalkyl, [0093] phenyl, [0094]
--SO.sub.2CH.sub.3, [0095] --C(.dbd.O)C.sub.1-4 alkoxy, [0096]
--C(.dbd.O)C.sub.1-4 alkyl, or [0097] --NR.sup.gC(.dbd.O)C.sub.1-4
alkyl; and [0098] each R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e,
R.sup.f, R.sup.g, R.sup.h, R.sup.i, and R.sup.j is independently
selected from H, and C.sub.1-4 alkyl.
[0099] In one aspect, the compounds of the invention are inhibitors
of autotaxin. Furthermore, the compounds of the invention may
exhibit low clearance, possibly resulting in low therapeutic dose
levels.
[0100] In a more particular aspect, the compounds of the invention
are active in vivo against IPF and/or COPD.
[0101] In a particular aspect, the compounds of the invention are
provided for use in the prophylaxis and/or treatment of fibrotic
diseases, proliferative diseases, inflammatory diseases, autoimmune
diseases, respiratory diseases, cardiovascular diseases,
neurodegenerative diseases, dermatological disorders, and/or
abnormal angiogenesis associated diseases.
[0102] In yet another aspect, the present invention provides a
method of treating a mammal having, or at risk of having a disease
disclosed herein. In a particular aspect, the present invention
provides a method of treating a mammal having, or at risk of having
fibrotic diseases, proliferative diseases, inflammatory diseases,
autoimmune diseases, respiratory diseases, cardiovascular diseases,
neurodegenerative diseases, dermatological disorders, and/or
abnormal angiogenesis associated diseases.
[0103] In a further aspect, the present invention provides
pharmaceutical compositions comprising a compound of the invention,
and a pharmaceutical carrier, excipient or diluent. In a particular
aspect, the pharmaceutical composition may additionally comprise
further therapeutically active ingredients suitable for use in
combination with the compounds of the invention. In a more
particular aspect, the further therapeutically active ingredient is
an agent for the treatment of fibrotic diseases, proliferative
diseases, inflammatory diseases, autoimmune diseases, respiratory
diseases, cardiovascular diseases, neurodegenerative diseases,
dermatological disorders, and/or abnormal angiogenesis associated
diseases.
[0104] Moreover, the compounds of the invention, useful in the
pharmaceutical compositions and treatment methods disclosed herein,
are pharmaceutically acceptable as prepared and used.
[0105] In a further aspect of the invention, this invention
provides a method of treating a mammal, in particular humans,
afflicted with a condition selected from among those listed herein,
and particularly fibrotic diseases, proliferative diseases,
inflammatory diseases, autoimmune diseases, respiratory diseases,
cardiovascular diseases, neurodegenerative diseases, dermatological
disorders, and/or abnormal angiogenesis associated diseases, which
method comprises administering an effective amount of the
pharmaceutical composition or compounds of the invention as
described herein.
[0106] The present invention also provides pharmaceutical
compositions comprising a compound of the invention, and a suitable
pharmaceutical carrier, excipient or diluent for use in medicine.
In a particular aspect, the pharmaceutical composition is for use
in the prophylaxis and/or treatment of fibrotic diseases,
proliferative diseases, inflammatory diseases, autoimmune diseases,
respiratory diseases, cardiovascular diseases, neurodegenerative
diseases, dermatological disorders, and/or abnormal angiogenesis
associated diseases.
[0107] In additional aspects, this invention provides methods for
synthesizing the compounds of the invention, with representative
synthetic protocols and pathways disclosed later on herein.
[0108] Other objects and advantages will become apparent to those
skilled in the art from a consideration of the ensuing detailed
description.
[0109] It will be appreciated that compounds of the invention may
be metabolized to yield biologically active metabolites.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0110] The following terms are intended to have the meanings
presented therewith below and are useful in understanding the
description and intended scope of the present invention.
[0111] When describing the invention, which may include compounds,
pharmaceutical compositions containing such compounds and methods
of using such compounds and compositions, the following terms, if
present, have the following meanings unless otherwise indicated. It
should also be understood that when described herein any of the
moieties defined forth below may be substituted with a variety of
substituents, and that the respective definitions are intended to
include such substituted moieties within their scope as set out
below. Unless otherwise stated, the term `substituted` is to be
defined as set out below. It should be further understood that the
terms `groups` and `radicals` can be considered interchangeable
when used herein.
[0112] The articles `a` and `an` may be used herein to refer to one
or to more than one (i.e. at least one) of the grammatical objects
of the article. By way of example `an analogue` means one analogue
or more than one analogue.
[0113] As used herein the term `LPA` relates to lysophosphatidic
acid which is a member of the membrane-derived bioactive lipid
mediators, further comprising sphingosine-1-phosphate (S1P),
lysophosphatidylcholine (LPC), and sphingosylphosphorylcholine
(SPC). LPA interacts with specific G protein-coupled receptors
(GPCRs), namely LPA.sub.1, LPA.sub.2, LPA.sub.3, LPA.sub.4,
LPA.sub.5, LPA.sub.6, LPA.sub.7, LPA.sub.8, in an autocrine and
paracrine fashion, to activate intracellular signaling pathways,
and in turn produce a variety of biological responses.
[0114] `Alkyl` means straight or branched aliphatic hydrocarbon
with the number of carbon atoms specified. Particular alkyl groups
have 1 to 8 carbon atoms. More particular is lower alkyl which has
1 to 6 carbon atoms. A further particular group has 1 to 4 carbon
atoms. Exemplary straight chained groups include methyl, ethyl
n-propyl, and n-butyl. Branched means that one or more lower alkyl
groups such as methyl, ethyl, propyl or butyl is attached to a
linear alkyl chain, exemplary branched chain groups include
isopropyl, iso-butyl, t-butyl and isoamyl.
[0115] `Alkoxy` refers to the group --OR.sup.26 where R.sup.26 is
alkyl with the number of carbon atoms specified. Particular alkoxy
groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and
1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e.
with between 1 and 6 carbon atoms. Further particular alkoxy groups
have between 1 and 4 carbon atoms.
[0116] `Alkylene` refers to divalent alkene radical groups having
the number of carbon atoms specified, in particular having 1 to 6
carbon atoms and more particularly 1 to 4 carbon atoms which can be
straight-chained or branched. This term is exemplified by groups
such as methylene (--CH.sub.2--), ethylene
(--CH.sub.2--CH.sub.2--), or --CH(CH.sub.3)-- and the like.
[0117] `Alkenyl` refers to monovalent olefinically (unsaturated)
hydrocarbon groups with the number of carbon atoms specified.
Particular alkenyl has 2 to 8 carbon atoms, and more particularly,
from 2 to 6 carbon atoms, which can be straight-chained or branched
and having at least 1 and particularly from 1 to 2 sites of
olefinic unsaturation. Particular alkenyl groups include ethenyl
(--CH.dbd.CH.sub.2), n-propenyl (--CH.sub.2CH.dbd.CH.sub.2),
isopropenyl (--C(CH.sub.3).dbd.CH.sub.2) and the like.
[0118] `Amino` refers to the radical --NH.sub.2.
[0119] `Aryl` refers to a monovalent aromatic hydrocarbon group
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. In particular aryl refers to
an aromatic ring structure, monocyclic or polycyclic, with the
number of ring atoms specified. Specifically, the term includes
groups that include from 6 to 10 ring members. Where the aryl group
is a monocyclic ring system it preferentially contains 6 carbon
atoms. Particularly aryl groups include phenyl, naphthyl, indenyl,
and tetrahydronaphthyl.
[0120] `Cycloalkyl` refers to a non-aromatic hydrocarbyl ring
structure, monocyclic or polycyclic, with the number of ring atoms
specified. A cycloalkyl may have from 3 to 10 carbon atoms, and in
particular from 3 to 7 carbon atoms. Such cycloalkyl groups
include, by way of example, single ring structures such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cycloheptyl.
[0121] `Cyano` refers to the radical --CN.
[0122] `Halo` or `halogen` refers to fluoro (F), chloro (Cl), bromo
(Br) and iodo (I). Particular halo groups are either fluoro or
chloro.
[0123] `Hetero` when used to describe a compound or a group present
on a compound means that one or more carbon atoms in the compound
or group have been replaced by a nitrogen, oxygen, or sulfur
heteroatom. Hetero may be applied to any of the hydrocarbyl groups
described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g.
heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1
to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or
2 heteroatoms, for example a single heteroatom.
[0124] `Heteroaryl` means an aromatic ring structure, monocyclic or
polycyclic, that includes one or more heteroatoms independently
selected from O, N and S and the number of ring atoms specified. In
particular, the aromatic ring structure may have from 5 to 10 ring
members. The heteroaryl group can be, for example, a five membered
or six membered monocyclic ring or a bicyclic structure formed from
fused five and six membered rings or two fused six membered rings
or, by way of a further example, two fused five membered rings.
Each ring may contain up to four heteroatoms typically selected
from nitrogen, sulphur and oxygen. Typically the heteroaryl ring
will contain up to 4 heteroatoms, more typically up to 3
heteroatoms, more usually up to 2, for example a single heteroatom.
In one embodiment, the heteroaryl ring contains at least one ring
nitrogen atom. The nitrogen atoms in the heteroaryl rings can be
basic, as in the case of an imidazole or pyridine, or essentially
non-basic as in the case of an indole or pyrrole nitrogen. In
general the number of basic nitrogen atoms present in the
heteroaryl group, including any amino group substituents of the
ring, will be less than five. Examples of five membered monocyclic
heteroaryl groups include but are not limited to pyrrole, furan,
thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole,
isoxazole, thiazole, isothiazole, thiadiazole, pyrazole, triazole
and tetrazole groups. Examples of six membered monocyclic
heteroaryl groups include but are not limited to pyridine,
pyrazine, pyridazine, pyrimidine and triazine. Particular examples
of bicyclic heteroaryl groups containing a five membered ring fused
to another five membered ring include but are not limited to
imidazothiazole and imidazoimidazole. Particular examples of
bicyclic heteroaryl groups containing a six membered ring fused to
a five membered ring include but are not limited to benzofuran,
benzothiophene, benzoimidazole, benzoxazole, isobenzoxazole,
benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran,
indole, isoindole, isoindolone, indolizine, indoline, isoindoline,
purine (e.g. adenine, guanine), indazole, imidazopyridines,
imidazopyrimidines, imidazopyrazines, pyrazolopyrimidine,
triazolopyrimidine, benzodioxole and pyrazolopyridine groups.
Particular examples of bicyclic heteroaryl groups containing two
fused six membered rings include but are not limited to quinoline,
isoquinoline, chroman, thiochroman, chromene, isochromene, chroman,
isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine,
pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine,
naphthyridine and pteridine groups. Particular heteroaryl groups
are those derived from thiophene, pyrrole, benzothiophene,
benzofuran, indole, pyridine, quinoline, imidazole, thiazole,
oxazole and pyrazine.
[0125] Examples of representative heteroaryls include the
following:
##STR00003##
wherein each Y is selected from >C(.dbd.O), NH, O and S.
[0126] As used herein, the term `heterocycloalkyl` means a stable
non-aromatic ring structure, mono-cyclic or polycyclic, that
includes one or more heteroatoms independently selected from O, N
and S and the number of ring atoms specified. The non-aromatic ring
structure may have from 4 to 10 ring members, and in particular
from 4 to 7 ring members. A fused heterocyclic ring system may
include carbocyclic rings and need only to include one heterocyclic
ring. Examples of heterocyclic rings include, but are not limited
to, morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl,
3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1-pyrrolidinyl,
2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran,
tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran
(e.g. 4-tetrahydro pyranyl), imidazoline, imidazolidinone,
oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazine, and
N-alkyl piperazines such as N-methyl piperazine. Further examples
include thiomorpholine and its S-oxide and S,S-dioxide
(particularly thiomorpholine). Still further examples include
azetidine, piperidone, piperazone, and N-alkyl piperidines such as
N-methyl piperidine. Particular examples of heterocycloalkyl groups
are shown in the following illustrative examples:
##STR00004##
wherein each W is selected from CH.sub.2, NH, O and S; and each Y
is selected from NH, O, C(.dbd.O), SO.sub.2, and S.
[0127] As used herein, the term `heterocycloalkenyl` means a
`heterocycloalkyl`, which comprises at least one double bond.
Particular examples of heterocycloalkenyl groups are shown in the
following illustrative examples:
##STR00005##
wherein each W is selected from CH.sub.2, NH, O and S; each Y is
selected from NH, O, C(.dbd.O), SO.sub.2, and S; and each Z is
selected from N or CH.
[0128] `Hydroxyl` refers to the radical --OH.
[0129] `Oxo` refers to the radical .dbd.O.
[0130] `Substituted` refers to a group in which one or more
hydrogen atoms are each independently replaced with the same or
different substituent(s).
[0131] `Sulfo` or `sulfonic acid` refers to a radical such as
--SO.sub.3H.
[0132] `Thiol` refers to the group --SH.
[0133] As used herein, term `substituted with one or more` refers
to one to four substituents. In one embodiment it refers to one to
three substituents. In further embodiments it refers to one or two
substituents. In a yet further embodiment it refers to one
substituent.
[0134] `Thioalkoxy` refers to the group --SR.sup.26 where R.sup.26
is alkyl with the number of carbon atoms specified. Particular
thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy,
isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, sec-thiobutoxy,
n-thiopentoxy, n-thiohexoxy, and 1,2-dimethylthiobutoxy. More
particular thioalkoxy groups are lower thioalkoxy, i.e. with
between 1 and 6 carbon atoms. Further particular alkoxy groups have
between 1 and 4 carbon atoms.
[0135] One having ordinary skill in the art of organic synthesis
will recognize that the maximum number of heteroatoms in a stable,
chemically feasible heterocyclic ring, whether it is aromatic or
non aromatic, is determined by the size of the ring, the degree of
unsaturation and the valence of the heteroatoms. In general, a
heterocyclic ring may have one to four heteroatoms so long as the
heteroaromatic ring is chemically feasible and stable.
[0136] `Pharmaceutically acceptable` means approved or approvable
by a regulatory agency of the Federal or a state government or the
corresponding agency in countries other than the United States, or
that is listed in the U.S. Pharmacopoeia or other generally
recognized pharmacopoeia for use in animals, and more particularly,
in humans.
[0137] `Pharmaceutically acceptable salt` refers to a salt of a
compound of the invention that is pharmaceutically acceptable and
that possesses the desired pharmacological activity of the parent
compound. In particular, such salts are non-toxic may be inorganic
or organic acid addition salts and base addition salts.
Specifically, such salts include: (1) acid addition salts, formed
with inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or
formed with organic acids such as acetic acid, propionic acid,
hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; or (2) salts formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
e.g. an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine and the like.
Salts further include, by way of example only, sodium, potassium,
calcium, magnesium, ammonium, tetraalkylammonium, and the like; and
when the compound contains a basic functionality, salts of non
toxic organic or inorganic acids, such as hydrochloride,
hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the
like. The term `pharmaceutically acceptable cation` refers to an
acceptable cationic counter-ion of an acidic functional group. Such
cations are exemplified by sodium, potassium, calcium, magnesium,
ammonium, tetraalkylammonium cations, and the like.
[0138] `Pharmaceutically acceptable vehicle` refers to a diluent,
adjuvant, excipient or carrier with which a compound of the
invention is administered.
[0139] `Prodrugs` refers to compounds, including derivatives of the
compounds of the invention, which have cleavable groups and become
by solvolysis or under physiological conditions the compounds of
the invention which are pharmaceutically active in vivo. Such
examples include, but are not limited to, choline ester derivatives
and the like, N-alkylmorpholine esters and the like.
[0140] `Solvate` refers to forms of the compound that are
associated with a solvent, usually by a solvolysis reaction. This
physical association includes hydrogen bonding. Conventional
solvents include water, ethanol, acetic acid and the like. The
compounds of the invention may be prepared e.g. in crystalline form
and may be solvated or hydrated. Suitable solvates include
pharmaceutically acceptable solvates, such as hydrates, and further
include both stoichiometric solvates and non-stoichiometric
solvates. In certain instances the solvate will be capable of
isolation, for example when one or more solvent molecules are
incorporated in the crystal lattice of the crystalline solid.
`Solvate` encompasses both solution-phase and isolable solvates.
Representative solvates include hydrates, ethanolates and
methanolates.
[0141] `Subject` includes humans. The terms `human`, `patient` and
`subject` are used interchangeably herein.
[0142] `Effective amount` means the amount of a compound of the
invention that, when administered to a subject for treating a
disease, is sufficient to effect such treatment for the disease.
The `effective amount` can vary depending on the compound, the
disease and its severity, and the age, weight, etc., of the subject
to be treated.
[0143] `Preventing` or `prevention` refers to a reduction in risk
of acquiring or developing a disease or disorder (i.e. causing at
least one of the clinical symptoms of the disease not to develop in
a subject that may be exposed to a disease-causing agent, or
predisposed to the disease in advance of disease onset).
[0144] The term `prophylaxis` is related to `prevention`, and
refers to a measure or procedure the purpose of which is to
prevent, rather than to treat or cure a disease. Non-limiting
examples of prophylactic measures may include the administration of
vaccines; the administration of low molecular weight heparin to
hospital patients at risk for thrombosis due, for example, to
immobilization; and the administration of an anti-malarial agent
such as chloroquine, in advance of a visit to a geographical region
where malaria is endemic or the risk of contracting malaria is
high.
[0145] `Treating` or `treatment` of any disease or disorder refers,
in one embodiment, to ameliorating the disease or disorder (i.e.
arresting the disease or reducing the manifestation, extent or
severity of at least one of the clinical symptoms thereof). In
another embodiment `treating` or `treatment` refers to ameliorating
at least one physical parameter, which may not be discernible by
the subject. In yet another embodiment, `treating` or `treatment`
refers to modulating the disease or disorder, either physically,
(e.g. stabilization of a discernible symptom), physiologically
(e.g. stabilization of a physical parameter), or both. In a further
embodiment, `treating` or `treatment` relates to slowing the
progression of the disease.
[0146] As used herein the term `fibrotic diseases` refers to
diseases characterized by excessive scarring due to excessive
production, deposition, and contraction of extracellular matrix,
and are that are associated with the abnormal accumulation of cells
and/or fibronectin and/or collagen and/or increased fibroblast
recruitment and include but are not limited to fibrosis of
individual organs or tissues such as the heart, kidney, liver,
joints, lung, pleural tissue, peritoneal tissue, skin, cornea,
retina, musculoskeletal and digestive tract. In particular, the
term fibrotic diseases refers to idiopathic pulmonary fibrosis
(IPF); cystic fibrosis, other diffuse parenchymal lung diseases of
different etiologies including iatrogenic drug-induced fibrosis,
occupational and/or environmental induced fibrosis, granulomatous
diseases (sarcoidosis, hypersensitivity pneumonia), collagen
vascular disease, alveolar proteinosis, langerhans cell
granulomatosis, lymphangioleiomyomatosis, inherited diseases
(Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis,
metabolic storage disorders, familial interstitial lung disease);
radiation induced fibrosis; chronic obstructive pulmonary disease
(COPD); scleroderma; bleomycin induced pulmonary fibrosis; chronic
asthma; silicosis; asbestos induced pulmonary fibrosis; acute
respiratory distress syndrome (ARDS); kidney fibrosis;
tubulointerstitium fibrosis; glomerular nephritis; focal segmental
glomerular sclerosis; IgA nephropathy; hypertension; Alport; gut
fibrosis; liver fibrosis; cirrhosis; alcohol induced liver
fibrosis; toxic/drug induced liver fibrosis; hemochromatosis;
nonalcoholic steatohepatitis (NASH); biliary duct injury; primary
biliary cirrhosis; infection induced liver fibrosis; viral induced
liver fibrosis; and autoimmune hepatitis; corneal scarring;
hypertrophic scarring; Dupuytren disease, keloids, cutaneous
fibrosis; cutaneous scleroderma; systemic sclerosis, spinal cord
injury/fibrosis; myelofibrosis; vascular restenosis;
atherosclerosis; arteriosclerosis; Wegener's granulomatosis;
Peyronie's disease, or chronic lymphocytic. More particularly, the
term `fibrotic diseases` refers to idiopathic pulmonary fibrosis
(IPF).
[0147] As used herein the term `proliferative disease(s)` refers to
conditions such as cancer (e.g. uterine leiomyosarcoma or prostate
cancer), myeloproliferative disorders (e.g. polycythemia vera,
essential thrombocytosis and myelofibrosis), leukemia (e.g. acute
myeloid leukaemia, acute and chronic lymphoblastic leukemia),
multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis.
In particular the term refers to cancer, leukemia, multiple myeloma
and psoriasis.
[0148] As used herein, the term `cancer` refers to a malignant or
benign growth of cells in skin or in body organs, for example but
without limitation, breast, prostate, lung, kidney, pancreas,
stomach or bowel. A cancer tends to infiltrate into adjacent tissue
and spread (metastasise) to distant organs, for example to bone,
liver, lung or the brain. As used herein the term cancer includes
both metastatic tumour cell types (such as but not limited to,
melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and
mastocytoma) and types of tissue carcinoma (such as but not limited
to, colorectal cancer, prostate cancer, small cell lung cancer and
non-small cell lung cancer, breast cancer, pancreatic cancer,
bladder cancer, renal cancer, gastric cancer, glioblastoma, primary
liver cancer, ovarian cancer, prostate cancer and uterine
leiomyosarcoma). In particular, the term `cancer` refers to acute
lymphoblastic leukemia, acute myeloidleukemia, adrenocortical
carcinoma, anal cancer, appendix cancer, astrocytomas, atypical
teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer,
bladder cancer, bone cancer (osteosarcoma and malignant fibrous
histiocytoma), brain stem glioma, brain tumors, brain and spinal
cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma,
cervical cancer, chronic lymphocytic leukemia, chronic myelogenous
leukemia, colon cancer, colorectal cancer, craniopharyngioma,
cutaneous T-Cell lymphoma, embryonal tumors, endometrial cancer,
ependymoblastoma, ependymoma, esophageal cancer, ewing sarcoma
family of tumors, eye cancer, retinoblastoma, gallbladder cancer,
gastric (stomach) cancer, gastrointestinal carcinoid tumor,
gastrointestinal stromal tumor (GIST), gastrointestinal stromal
cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and
neck cancer, hepatocellular (liver) cancer, hodgkin lymphoma,
hypopharyngeal cancer, intraocular melanoma, islet cell tumors
(endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans
cell histiocytosis, laryngeal cancer, leukemia, Acute lymphoblastic
leukemia, acute myeloid leukemia, chronic lymphocytic leukemia,
chronic myelogenous leukemia, hairy cell leukemia, liver cancer,
non-small cell lung cancer, small cell lung cancer, Burkitt
lymphoma, cutaneous T-celllymphoma, Hodgkin lymphoma, non-Hodgkin
lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma,
medulloepithelioma, melanoma, mesothelioma, mouth cancer, chronic
myelogenous leukemia, myeloid leukemia, multiple myeloma,
asopharyngeal cancer, neuroblastoma, non-small cell lung cancer,
oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous
histiocytoma of bone, ovarian cancer, ovarian epithelial cancer,
ovarian germ cell tumor, ovarian low malignant potential tumor,
pancreatic cancer, papillomatosis, parathyroid cancer, penile
cancer, pharyngeal cancer, pineal parenchymal tumors of
intermediate differentiation, pineoblastoma and supratentorial
primitive neuroectodermal tumors, pituitary tumor, plasma cell
neoplasm/multiple myeloma, pleuropulmonary blastoma, primary
central nervous system lymphoma, prostate cancer, rectal cancer,
renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma,
salivary gland cancer, sarcoma, Ewing sarcoma family of tumors,
sarcoma, kaposi, Sezary syndrome, skin cancer, small cell Lung
cancer, small intestine cancer, soft tissue sarcoma, squamous cell
carcinoma, stomach (gastric) cancer, supratentorial primitive
neuroectodermal tumors, T-cell lymphoma, testicular cancer, throat
cancer, thymoma and thymic carcinoma, thyroid cancer, urethral
cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar
cancer, Waldenstrom macroglobulinemia, and Wilms tumor
[0149] As used herein the term `leukemia` refers to neoplastic
diseases of the blood and blood forming organs. Such diseases can
cause bone marrow and immune system dysfunction, which renders the
host highly susceptible to infection and bleeding. In particular
the term leukemia refers to acute myeloid leukaemia (AML), and
acute lymphoblastic leukemia (ALL) and chronic lymphoblastic
leukaemia (CLL).
[0150] As used herein the term `inflammatory diseases` refers to
the group of conditions including, rheumatoid arthritis,
osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic
arthritis, allergic airway disease (e.g. asthma, rhinitis), chronic
obstructive pulmonary disease (COPD), inflammatory bowel diseases
(e.g. Crohn's disease, ulcerative colitis), endotoxin-driven
disease states (e.g. complications after bypass surgery or chronic
endotoxin states contributing to e.g. chronic cardiac failure), and
related diseases involving cartilage, such as that of the joints.
Particularly the term refers to rheumatoid arthritis,
osteoarthritis, allergic airway disease (e.g. asthma), chronic
obstructive pulmonary disease (COPD) and inflammatory bowel
diseases (e.g. Crohn's disease and ulcerative colitis). More
particularly the term refers to rheumatoid arthritis, and chronic
obstructive pulmonary disease (COPD).
[0151] As used herein the term `autoimmune disease(s)` refers to
the group of diseases including obstructive airways disease,
including conditions such as COPD, asthma (e.g. intrinsic asthma,
extrinsic asthma, dust asthma, infantile asthma) particularly
chronic or inveterate asthma (for example late asthma and airway
hyperreponsiveness), bronchitis, including bronchial asthma,
systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis,
lupus nephritis, dermatomyositis, Sjogren's syndrome, multiple
sclerosis, psoriasis, dry eye disease, type I diabetes mellitus and
complications associated therewith, atopic eczema (atopic
dermatitis), thyroiditis (Hashimoto's and autoimmune thyroiditis),
contact dermatitis and further eczematous dermatitis, inflammatory
bowel disease (e.g. Crohn's disease and ulcerative colitis),
atherosclerosis and amyotrophic lateral sclerosis. Particularly the
term refers to COPD, asthma, systemic lupus erythematosis, type I
diabetes mellitus and inflammatory bowel disease.
[0152] As used herein, the term `respiratory disease` refers to
diseases affecting the organs that are involved in breathing, such
as the nose, throat, larynx, eustachian tubes, trachea, bronchi,
lungs, related muscles (e.g., diaphram and intercostals), and
nerves. In particular, examples of respiratory diseases include
asthma, adult respiratory distress syndrome and allergic
(extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe
asthma, chronic asthma, clinical asthma, nocturnal asthma,
allerGen-induced asthma, aspirin-sensitive asthma, exercise-induced
asthma, isocapnic hyperventilation, child onset asthma, adult-onset
asthma, cough-variant asthma, occupational asthma,
steroid-resistant asthma, seasonal asthma, seasonal allergic
rhinitis, perennial allergic rhinitis, chronic obstructive
pulmonary disease, including chronic bronchitis or emphysema,
pulmonary hypertension, interstitial lung fibrosis and/or airway
inflammation, cystic fibrosis, and hypoxia.
[0153] As used herein the term `allergy` refers to the group of
conditions characterized by a hypersensitivity disorder of the
immune system including, allergic airway disease (e.g. asthma,
rhinitis), sinusitis, eczema and hives, as well as food allergies
or allergies to insect venom.
[0154] As used herein the term `asthma` as used herein refers to
any disorder of the lungs characterized by variations in pulmonary
gas flow associated with airway constriction of whatever cause
(intrinsic, extrinsic, or both; allergic or non-allergic). The term
asthma may be used with one or more adjectives to indicate the
cause.
[0155] As used herein the term `cardiovascular disease` refers to
diseases affecting the heart or blood vessels or both. In
particular, cardiovascular disease includes arrhythmia (atrial or
ventricular or both); atherosclerosis and its sequelae; angina;
cardiac rhythm disturbances; myocardial ischemia; myocardial
infarction; cardiac or vascular aneurysm; vasculitis, stroke;
peripheral obstructive arteriopathy of a limb, an organ, or a
tissue; reperfusion injury following ischemia of the brain, heart,
kidney or other organ or tissue; endotoxic, surgical, or traumatic
shock; hypertension, valvular heart disease, heart failure,
abnormal blood pressure; vasoconstriction (including that
associated with migraines); vascular abnormality, inflammation,
insufficiency limited to a single organ or tissue.
[0156] As used herein the term `neurodegenerative diseases` refers
to disorders that are associated with atrophy of the affected
central or peripheral structures of the nervous system. In
particular, the term `neurodegenerative diseases` refers to
diseases such as Alzheimer's disease and other dementias,
degenerative nerve diseases, encephalitis, epilepsy, genetic brain
disorders, head and brain malformations, hydrocephalus, stroke,
Parkinson's disease, multiple sclerosis, amyotrophic lateral
sclerosis (ALS or Lou Gehrig's Disease), Huntington's disease, and
prion diseases.
[0157] As used herein the term `dermatological disorder` refers to
a skin disorder. In particular, dermatological disorders include
proliferative or inflammatory disorders of the skin such as, atopic
dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic
lesions, dermatitis, contact dermatitis, eczema, pruritus,
urticaria, rosacea, scleroderma, wound healing, scarring,
hypertrophic scarring, keloids, Kawasaki Disease, rosacea,
Sjogren-Larsso Syndrome, or urticaria.
[0158] As used herein the term `abnormal angiogenesis associated
disease` refers to diseases caused by the dysregulation of the
processes mediating angiogenesis. In particular, abnormal
angiogenesis associated disease refers to atherosclerosis,
hypertension, tumor growth, inflammation, rheumatoid arthritis,
wet-form macular degeneration, choroidal neovascularization,
retinal neovascularization, and diabetic retinopathy.
[0159] `Compound(s) of the invention`, and equivalent expressions,
are meant to embrace compounds of the Formula(e) as herein
described, which expression includes the pharmaceutically
acceptable salts, and the solvates, e.g. hydrates, and the solvates
of the pharmaceutically acceptable salts where the context so
permits. Similarly, reference to intermediates, whether or not they
themselves are claimed, is meant to embrace their salts, and
solvates, where the context so permits.
[0160] When ranges are referred to herein, for example but without
limitation, C.sub.1-8 alkyl, the citation of a range should be
considered a representation of each member of said range.
[0161] Other derivatives of the compounds of this invention have
activity in both their acid and acid derivative forms, but in the
acid sensitive form often offers advantages of solubility, tissue
compatibility, or delayed release in the mammalian organism
(Bundgaard 1992). Prodrugs include acid derivatives well know to
practitioners of the art, such as, for example, esters prepared by
reaction of the parent acid with a suitable alcohol, or amides
prepared by reaction of the parent acid compound with a substituted
or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
Simple aliphatic or aromatic esters, amides and anhydrides derived
from acidic groups pendant on the compounds of this invention are
particularly useful prodrugs. In some cases it is desirable to
prepare double ester type prodrugs such as (acyloxy)alkyl esters or
((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.6-10 optionally
substituted aryl, and (C.sub.6-10 aryl)-(C.sub.1-4 alkyl) esters of
the compounds of the invention.
[0162] As used herein, the term `isotopic variant` refers to a
compound that contains unnatural proportions of isotopes at one or
more of the atoms that constitute such compound. For example, an
`isotopic variant` of a compound can contain one or more
non-radioactive isotopes, such as for example, deuterium (.sup.2H
or D), carbon-13 (.sup.13C), nitroGen-15 (.sup.15N), or the like.
It will be understood that, in a compound where such isotopic
substitution is made, the following atoms, where present, may vary,
so that for example, any hydrogen may be .sup.2H/D, any carbon may
be .sup.13C, or any nitrogen may be .sup.15N, and that the presence
and placement of such atoms may be determined within the skill of
the art. Likewise, the invention may include the preparation of
isotopic variants with radioisotopes, in the instance for example,
where the resulting compounds may be used for drug and/or substrate
tissue distribution studies. The radioactive isotopes tritium, i.e.
.sup.3H, and carbon-14, i.e. .sup.14C, are particularly useful for
this purpose in view of their ease of incorporation and ready means
of detection. Further, compounds may be prepared that are
substituted with positron emitting isotopes, such as .sup.11C,
.sup.18F, .sup.15O, and .sup.13N, and would be useful in Positron
Emission Topography (PET) studies for examining substrate receptor
occupancy.
[0163] All isotopic variants of the compounds provided herein,
radioactive or not, are intended to be encompassed within the scope
of the invention.
[0164] It is also to be understood that compounds that have the
same molecular formula but differ in the nature or sequence of
bonding of their atoms or the arrangement of their atoms in space
are termed `isomers`. Isomers that differ in the arrangement of
their atoms in space are termed `stereoisomers`.
[0165] Stereoisomers that are not mirror images of one another are
termed `diastereomers` and those that are non-superimposable mirror
images of each other are termed `enantiomers`. When a compound has
an asymmetric center, for example, it is bonded to four different
groups, a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric
center and is described by the R- and S-sequencing rules of Cahn
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e. as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a `racemic mixture`.
[0166] `Tautomers` refer to compounds that are interchangeable
forms of a particular compound structure, and that vary in the
displacement of hydrogen atoms and electrons. Thus, two structures
may be in equilibrium through the movement of .pi. electrons and an
atom (usually H). For example, enols and ketones are tautomers
because they are rapidly interconverted by treatment with either
acid or base. Another example of tautomerism is the aci- and
nitro-forms of phenylnitromethane, that are likewise formed by
treatment with acid or base.
[0167] Tautomeric forms may be relevant to the attainment of the
optimal chemical reactivity and biological activity of a compound
of interest.
[0168] The compounds of the invention may possess one or more
asymmetric centers; such compounds can therefore be produced as
individual (R)- or (S)-stereoisomers or as mixtures thereof.
[0169] Unless indicated otherwise, the description or naming of a
particular compound in the specification and claims is intended to
include both individual enantiomers and mixtures, racemic or
otherwise, thereof. The methods for the determination of
stereochemistry and the separation of stereoisomers are well-known
in the art.
[0170] It will be appreciated that compounds of the invention may
be metabolized to yield biologically active metabolites.
The Invention
[0171] The present invention is based on the identification of
novel compounds, and their ability to act as inhibitors of
autotaxin and that they may be useful for the treatment of fibrotic
diseases, proliferative diseases, inflammatory diseases, autoimmune
diseases, respiratory diseases, cardiovascular diseases,
neurodegenerative diseases, dermatological disorders, and/or
abnormal angiogenesis associated diseases.
[0172] The present invention also provides methods for the
production of these compounds, pharmaceutical compositions
comprising these compounds and methods for the prophylaxis and/or
treatment of fibrotic diseases, proliferative diseases,
inflammatory diseases, autoimmune diseases, respiratory diseases,
cardiovascular diseases, neurodegenerative diseases, dermatological
disorders, and/or abnormal angiogenesis associated diseases by
administering the compounds of the invention.
[0173] Accordingly, in a first aspect of the invention, the
compounds of the invention are provided having a Formula (I):
##STR00006## [0174] wherein [0175] R.sup.1a is H, halo or C.sub.1-4
alkyl; [0176] R.sup.1b is: [0177] halo, [0178] C.sub.1-4 alkyl
(which alkyl is optionally substituted with one or more
independently selected halo), or [0179] C.sub.1-4 alkoxy (which
alkoxy is optionally substituted with one or more independently
selected halo); [0180] X is --S--, --O--, --N.dbd.CH--,
--CH.dbd.N-- or --CH.dbd.CH--; [0181] W is N, or CR.sup.3 [0182]
when W is N, R.sup.2 is: [0183] H, [0184] --CN, [0185] halo, [0186]
C.sub.1-4 alkyl (which alkyl is optionally substituted with one or
more independently selected OH, or CN), [0187] --C(.dbd.O)CH.sub.3,
[0188] --C(.dbd.O)CF.sub.3, [0189] --C(.dbd.O)OCH.sub.3, [0190]
--C(.dbd.O)NH.sub.2, or [0191] --NHC(.dbd.O)CH.sub.3, or [0192]
when W is CR.sup.3, one of R.sup.2 or R.sup.3 is: [0193] H, [0194]
--CN, [0195] halo, [0196] C.sub.1-4 alkyl (which alkyl is
optionally substituted with one or more independently selected OH,
or CN), [0197] --C(.dbd.O)CH.sub.3, [0198] --C(.dbd.O)CF.sub.3,
[0199] --C(.dbd.O)OCH.sub.3, [0200] --C(.dbd.O)NH.sub.2, or [0201]
--NHC(.dbd.O)CH.sub.3, [0202] and the other is H, or C.sub.1-4
alkyl; [0203] R.sup.4 is C.sub.1-4 alkyl; [0204] R.sup.5 is
C.sub.1-4 alkyl optionally substituted with one or more
independently selected CN, OH, halo, or --C(.dbd.O)NH.sub.2; [0205]
one of Y and Z is CH and the other is N; [0206] R.sup.6 is selected
from H, --CH.sub.3 and halo; [0207] Cy is: [0208] C.sub.4-10
cycloalkyl, [0209] 4-10 membered mono or bicyclic heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, or [0210] 4-7 membered heterocycloalkenyl containing 1
double bond, containing one or more heteroatoms independently
selected from O, N, and S; [0211] each R.sup.7 is independently
selected from: [0212] OH, [0213] oxo, [0214] halo, and [0215]
C.sub.1-4 alkyl (which alkyl is optionally substituted with one or
more independently selected OH, or C.sub.1-4 alkoxy); [0216] the
subscript a is 0, 1 or 2; [0217] R.sup.8 is
-(L.sub.1-W.sub.1).sub.m-L.sub.2-G.sub.1, [0218] wherein [0219]
L.sub.1 is absent, or is --O--, --C(.dbd.O)--, --NR.sup.i,
--NR.sup.hC(.dbd.O)--, or --SO.sub.2--; [0220] W.sub.1 is C.sub.1-4
alkylene; [0221] the subscript m is 0, or 1; [0222] L.sub.2 is
absent, or is --O--, --C(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--,
--C(.dbd.O)--C(.dbd.O)--, --C(.dbd.O)--C(.dbd.O)NR.sup.a--,
--NR.sup.b--, --C(.dbd.O)NR.sup.c--, --NR.sup.dC(.dbd.O)--,
--NR.sup.jC(.dbd.O)O--, --SO.sub.2--, --SO.sub.2NR.sup.e-- or
--NR.sup.fSO.sub.2--; [0223] G.sub.1 is [0224] H, [0225] --CN,
[0226] C.sub.1-4 alkyl (which alkyl is optionally substituted with
one or more independently selected --CN, OH, halo or phenyl),
[0227] C.sub.3-7 cycloalkyl (which cycloalkyl is optionally
substituted with --NH.sub.2), [0228] 5-6 membered
heterocycloalkenyl containing 1 double bond containing one or more
heteroatoms independently selected from O, N, and S (which
heterocycloalkenyl is optionally substituted with one or more
independently selected R.sup.9 groups), [0229] 4-10 membered mono,
bi or spirocyclic heterocycloalkyl containing one or more
heteroatoms independently selected from O, N, and S (which
heterocycloalkyl is optionally substituted with one or more
independently selected R.sup.9 groups), or [0230] 5-6 membered
heteroaryl containing one or more heteroatoms independently
selected from O, N, and S (which heteroaryl is optionally
substituted with one or more independently selected R.sup.10
groups), or [0231] each R.sup.9 is oxo, or R.sup.10; [0232] each
R.sup.10 is: [0233] --OH, [0234] halo, [0235] --CN, [0236]
C.sub.1-4 alkyl (which alkyl is optionally substituted with one or
more independently selected OH, halo, or phenyl), [0237] C.sub.1-4
alkoxy, [0238] C.sub.3-7 cycloalkyl, [0239] phenyl, [0240]
--SO.sub.2CH.sub.3, [0241] --C(.dbd.O)C.sub.1-4 alkoxy, [0242]
--C(.dbd.O)C.sub.1-4 alkyl, or [0243] --NR.sup.gC(.dbd.O)C.sub.1-4
alkyl; and [0244] each R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e,
R.sup.f, R.sup.g, R.sup.h, R.sup.i, and R.sup.j is independently
selected from H, and C.sub.1-4 alkyl;
[0245] In one embodiment, a compound of the invention is according
to Formula I, wherein R.sup.1a is H.
[0246] In one embodiment, a compound of the invention is according
to Formula I, wherein R.sup.1a is halo. In a particular embodiment,
R.sup.1a is F, Cl, or Br. In a more particular embodiment, R.sup.1a
is F, or Cl. In a most particular embodiment, R.sup.1a is F.
[0247] In one embodiment, a compound of the invention is according
to Formula I, wherein R.sup.1a is C.sub.1-4 alkyl. In a particular
embodiment, R.sup.1a is --CH.sub.3, --CH.sub.2--CH.sub.3,
--CH.sub.2--CH.sub.2--CH.sub.3, --CH(CH.sub.3).sub.2. In a more
particular embodiment, R.sup.1a is --CH.sub.3, or
--CH.sub.2--CH.sub.3.
[0248] In one embodiment, a compound of the invention is according
to Formula I, wherein R.sup.1b is halo. In a particular embodiment,
R.sup.1b is F, Cl, or Br. In a more particular embodiment, R.sup.1b
is F, or Cl. In a most particular embodiment, R.sup.1b is F.
[0249] In one embodiment, a compound of the invention is according
to Formula I, wherein R.sup.1b is C.sub.1-4 alkyl. In a particular
embodiment, R.sup.1b is --CH.sub.3, --CH.sub.2--CH.sub.3,
--CH.sub.2--CH.sub.2--CH.sub.3, --CH(CH.sub.3).sub.2. In a more
particular embodiment, R.sup.1b is --CH.sub.3, or
--CH.sub.2--CH.sub.3.
[0250] In one embodiment, a compound of the invention is according
to Formula I, wherein R.sup.1b is C.sub.1-4 alkyl substituted with
one or more independently selected halo. In a particular
embodiment, R.sup.1b is --CF.sub.3, or --CH.sub.2--CF.sub.3. In a
more particular embodiment, R.sup.1b is --CF.sub.3.
[0251] In one embodiment, a compound of the invention is according
to Formula I, wherein R.sup.1b is C.sub.1-4 alkoxy. In a particular
embodiment, R.sup.1b is --OCH.sub.3, --OCH.sub.2--CH.sub.3,
--OCH.sub.2--CH.sub.2--CH.sub.3, --OCH(CH.sub.3).sub.2. In a more
particular embodiment, R.sup.1b is --OCH.sub.3, or
--OCH.sub.2--CH.sub.3. In a most particular embodiment, R.sup.1b is
--OCH.sub.3.
[0252] In one embodiment, a compound of the invention is according
to Formula I, wherein R.sup.1b is C.sub.1-4 alkoxy substituted with
one or more independently selected halo. In a more particular
embodiment, R.sup.1b is --OCF.sub.3, --OCH.sub.2--CHF.sub.2 or
--OCH.sub.2--CF.sub.3. In a most particular embodiment, R.sup.1b is
--OCF.sub.3.
[0253] In one embodiment, a compound of the invention is according
to Formula I, wherein X is --S--, --O--, --N.dbd.CH--, --CH.dbd.N--
or --CH.dbd.CH--. In a particular embodiment, X is --S--, or
--O--.
[0254] In one embodiment, a compound of the invention is according
to Formula I, wherein W is N, and R.sup.2 is as previously defined.
In a particular embodiment, R.sup.2 is H, --CN,
--C(.dbd.O)CH.sub.3, --C(.dbd.O)CF.sub.3, --C(.dbd.O)OCH.sub.3,
--C(.dbd.O)NH.sub.2, or --NHC(.dbd.O)CH.sub.3. In a more particular
embodiment, R.sup.2 is --CN.
[0255] In one embodiment, a compound of the invention is according
to Formula I, wherein W is N, and R.sup.2 is as previously defined.
In a particular embodiment, R.sup.2 is halo. In a more particular
embodiment, R.sup.2 is F, Cl, or Br. In a most particular
embodiment, R.sup.2 is F, or Cl.
[0256] In one embodiment, a compound of the invention is according
to Formula I, wherein W is N, and R.sup.2 is as previously defined.
In a particular embodiment, R.sup.2 is C.sub.1-4 alkyl. In another
particular embodiment, R.sup.2 is C.sub.1-4 alkyl substituted with
one or more independently selected OH, and CN. In yet another
particular embodiment, R.sup.2 is C.sub.1-4 alkyl substituted with
one OH, or CN. In a more particular embodiment, R.sup.2 is
--CH.sub.3, --CH.sub.2--CH.sub.3, --CH.sub.2--OH, or
--CH.sub.2--CN. In a most particular embodiment, R.sup.2 is
--CH.sub.2--OH, or --CH.sub.2--CN.
[0257] In another embodiment, a compound of the invention is
according to Formula I, wherein W is CR.sup.3, and R.sup.2 and
R.sup.3 are as previously defined. In a particular embodiment,
R.sup.2 is H, --CN, --C(.dbd.O)CH.sub.3, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, or
--NHC(.dbd.O)CH.sub.3, and R.sup.3 is H, or C.sub.1-4 alkyl. In
another particular embodiment, R.sup.2 is H, or C.sub.1-4 alkyl,
and R.sup.3 is H, --CN, --C(.dbd.O)CH.sub.3, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, or
--NHC(.dbd.O)CH.sub.3. In a more particular embodiment, R.sup.2 is
H, --CN, --C(.dbd.O)CH.sub.3, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, or
--NHC(.dbd.O)CH.sub.3, and R.sup.3 is H, --CH.sub.3, or
--CH.sub.2--CH.sub.3. In another more particular embodiment,
R.sup.2 is H, --CH.sub.3, or --CH.sub.2--CH.sub.3, and R.sup.3 is
H, --CN, --C(.dbd.O)CH.sub.3, --C(.dbd.O)CF.sub.3,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)NH.sub.2, or
--NHC(.dbd.O)CH.sub.3. In a most particular embodiment, R.sup.2 is
--CN, and R.sup.3 is H, --CH.sub.3, or --CH.sub.2--CH.sub.3. In
another most particular embodiment, R.sup.2 is H, --CH.sub.3, or
--CH.sub.2--CH.sub.3, and R.sup.3 is --CN.
[0258] In another embodiment, a compound of the invention is
according to Formula I, wherein W is CR.sup.3, and R.sup.2 and
R.sup.3 are as previously defined. In a particular embodiment,
R.sup.2 is halo, and R.sup.3 is H, or C.sub.1-4 alkyl. In another
particular embodiment, R.sup.2 is H, or C.sub.1-4 alkyl, and
R.sup.3 is halo. In a more particular embodiment, R.sup.2 is F, Cl,
or Br, and R.sup.3 is H, --CH.sub.3, or --CH.sub.2--CH.sub.3. In
another more particular embodiment, R.sup.2 is H, --CH.sub.3, or
--CH.sub.2--CH.sub.3, and R.sup.3 is F, Cl, or Br. In a most
particular embodiment, R.sup.2 is F, or Cl, and R.sup.3 is H,
--CH.sub.3, or --CH.sub.2--CH.sub.3. In another most particular
embodiment, R.sup.2 is H, --CH.sub.3, or --CH.sub.2--CH.sub.3, and
R.sup.3 is F, or Cl.
[0259] In another embodiment, a compound of the invention is
according to Formula I, wherein W is CR.sup.3, and R.sup.2 and
R.sup.3 are as previously defined. In a particular embodiment,
R.sup.2 is C.sub.1-4 alkyl, and R.sup.3 is H, or C.sub.1-4 alkyl.
In another particular embodiment, R.sup.2 is H, or C.sub.1-4 alkyl,
and R.sup.3 is C.sub.1-4 alkyl. In a more particular embodiment,
R.sup.2 is --CH.sub.3, or --CH.sub.2--CH.sub.3, and R.sup.3 is H,
--CH.sub.3, or --CH.sub.2--CH.sub.3. In another more particular
embodiment, R.sup.2 is H, --CH.sub.3, or --CH.sub.2--CH.sub.3, and
R.sup.3 is --CH.sub.3, or --CH.sub.2--CH.sub.3.
[0260] In another embodiment, a compound of the invention is
according to Formula I, wherein W is CR.sup.3, and R.sup.2 and
R.sup.3 are as previously defined. In a particular embodiment,
R.sup.2 is C.sub.1-4 alkyl substituted with OH, or CN, and R.sup.3
is H, or C.sub.1-4 alkyl. In another particular embodiment, R.sup.2
is H, or C.sub.1-4 alkyl, and R.sup.3 is C.sub.1-4 alkyl
substituted with OH, or CN. In a more particular embodiment,
R.sup.2 is --CH.sub.2--OH, or --CH.sub.2--CN, and R.sup.3 is H,
--CH.sub.3, or --CH.sub.2--CH.sub.3. In another more particular
embodiment, R.sup.2 is H, --CH.sub.3, or --CH.sub.2--CH.sub.3, and
R.sup.3 is --CH.sub.2--OH, or --CH.sub.2--CN.
[0261] In one embodiment, a compound of the invention is according
to Formula II:
##STR00007##
[0262] wherein the subscript a, Y, Z, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, and R.sup.8 are as described above.
[0263] In another embodiment, a compound of the invention is
according to Formula III:
##STR00008##
[0264] wherein the subscript a, Y, Z, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, and R.sup.8 are as described above.
[0265] In one embodiment, a compound of the invention is according
to Formula I, II or III, wherein R.sup.4 is C.sub.1-4 alkyl. In a
particular embodiment, R.sup.4 is --CH.sub.3, or
--CH.sub.2--CH.sub.3. In a more particular embodiment, R.sup.4 is
--CH.sub.3.
[0266] In one embodiment, a compound of the invention is according
to Formula I, II or III, wherein R.sup.5 is C.sub.1-4 alkyl. In a
particular embodiment, R.sup.5 is --CH.sub.3, --CH.sub.2--CH.sub.3
or --CH.sub.2--CH.sub.2--CH.sub.3. In a more particular embodiment,
R.sup.5 is --CH.sub.3, or --CH.sub.2--CH.sub.3. In a most
particular embodiment, R.sup.5 is --CH.sub.2--CH.sub.3.
[0267] In one embodiment, a compound of the invention is according
to Formula I, II or III, wherein R.sup.5 is C.sub.1-4 alkyl
substituted with one or more independently selected CN, OH, halo,
and --C(.dbd.O)NH.sub.2. In a particular embodiment, R.sup.5 is
C.sub.1-4 alkyl substituted with one CN, OH, halo, or
--C(.dbd.O)NH.sub.2. In a more particular embodiment, R.sup.5 is
--CH.sub.3, --CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2--CH.sub.3,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3, --CH(CH.sub.3).sub.2, or
--CH.sub.2--CH(CH.sub.3).sub.2, each of which is substituted with
one CN, OH, halo, or --C(.dbd.O)NH.sub.2. In another more
particular embodiment, R.sup.5 is --CH.sub.3, --CH.sub.2--CH.sub.3,
--CH.sub.2--CH.sub.2--CH.sub.3,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3, or
--CH.sub.2--CH(CH.sub.3).sub.2, each of which is substituted with
one --CN, OH, F, or --C(.dbd.O)NH.sub.2. In a most particular
embodiment, R.sup.5 is --CH.sub.2--CH.sub.2--CN,
--CH.sub.2--CH.sub.2--OH, --CH.sub.2--CF.sub.3, or
--CH.sub.2--CH.sub.2--C(.dbd.O)NH.sub.2.
[0268] In one embodiment, a compound of the invention is according
to Formula I, II or III, wherein Cy is C.sub.3-10 cycloalkyl. In a
particular embodiment, Cy is cyclobutyl, cyclopentyl or cyclohexyl.
In a more particular embodiment, Cy is cyclohexyl.
[0269] In one embodiment, a compound of the invention is according
to Formula I, II or III, wherein Cy is 4-10 membered mono or
bicyclic heterocycloalkyl containing one or more heteroatoms
independently selected from O, N, and S. In a particular
embodiment, Cy is oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, or thiomorpholinyl. In a more particular embodiment,
Cy is piperidinyl. In another more particular embodiment, Cy is
piperazinyl.
[0270] In one embodiment, a compound of the invention is according
to Formula I, II or III, wherein Cy is 4-7 membered
heterocycloalkenyl containing 1 double bond, containing one or more
heteroatoms independently selected from O, N, and S. In a
particular embodiment, Cy is dihydrofuranyl, dihydrothiazolyl,
dihydrooxazolyl, dihydropyranyl, tetrahydropyridinyl, or
dihydrothiopyranyl. In a more particular embodiment, Cy is
dihydrooxazolyl.
[0271] In one embodiment, a compound of the invention is according
to Formula I, II or III, wherein the subscript a is 1 or 2, and
R.sup.7 is OH, oxo, or halo. In a particular embodiment, R.sup.7 is
OH, oxo, F, or Cl.
[0272] In one embodiment, a compound of the invention is according
to Formula I, II or III, wherein the subscript a is 1 or 2, and
R.sup.7 is C.sub.1-4 alkyl. In a particular embodiment, R.sup.7 is
--CH.sub.3, --CH.sub.2--CH.sub.3, or --CH(CH.sub.3).sub.2. In a
more particular embodiment, R.sup.7 is --CH.sub.3.
[0273] In one embodiment, a compound of the invention is according
to Formula I, II or III, wherein the subscript a is 1 or 2, and
R.sup.7 is C.sub.1-4 alkyl substituted with OH, or C.sub.1-4
alkoxy. In a particular embodiment, R.sup.7 is --CH.sub.3,
--CH.sub.2--CH.sub.3, or --CH(CH.sub.3).sub.2, each of which is
substituted with OH, or C.sub.1-4 alkoxy. In a more particular
embodiment, R.sup.7 is --CH.sub.2--OH, or
--CH.sub.2--OCH.sub.3.
[0274] In one embodiment, a compound of the invention is according
to Formula I, II or III, wherein the subscript a is 0.
[0275] In one embodiment, a compound of the invention is according
to Formula IVa, IVb, IVc or IVd:
##STR00009##
wherein Y, Z, R.sup.6, L.sub.1, W.sub.1, L.sub.2, G.sub.1 and the
subscript m are as previously described.
[0276] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein the subscript m is 1, and L.sub.1 is
absent.
[0277] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein the subscript m is 1, L.sub.1 is
--NR.sup.i--, and R.sup.i is as previously described. In a
particular embodiment, R.sup.i is H. In another particular
embodiment, R.sup.i is --CH.sub.3, --CH.sub.2--CH.sub.3, or
--CH(CH.sub.3).sub.2.
[0278] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein the subscript m is 1, L.sub.1 is
--NR.sup.hC(.dbd.O)--, and R.sup.h is as previously described. In a
particular embodiment, R.sup.h is H. In another particular
embodiment, R.sup.h is --CH.sub.3, --CH.sub.2--CH.sub.3, or
--CH(CH.sub.3).sub.2.
[0279] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein the subscript m is 1, and L.sub.1 is
--C(.dbd.O)--, or --SO.sub.2--.
[0280] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein the subscript m is 1, and W.sub.1 is
C.sub.1-4 alkylene. In a particular embodiment, W.sub.1 is
--CH.sub.2--, --CH.sub.2--CH.sub.2--, --C(CH.sub.3)H--,
--CH.sub.2--CH.sub.2--CH.sub.2-- or --CH.sub.2--C(CH.sub.3)H--. In
a more particular embodiment, W.sub.1 is --CH.sub.2--, or
--C(CH.sub.3)H--.
[0281] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein the subscript m is 0.
[0282] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein L.sub.2 is absent.
[0283] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein L.sub.2 is --O--.
[0284] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein L.sub.2 is --O--, --C(.dbd.O)--,
--C(.dbd.O)O--, --OC(.dbd.O)--, --C(.dbd.O)--C(.dbd.O)--, or
--SO.sub.2--.
[0285] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein L.sub.2 is
--C(.dbd.O)--C(.dbd.O)NR.sup.a--, and R.sup.a is as previously
described. In a particular embodiment, R.sup.a is H. In another
particular embodiment, R.sup.a is --CH.sub.3, --CH.sub.2--CH.sub.3,
or --CH(CH.sub.3).sub.2.
[0286] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein L.sub.2 is --NR.sup.b--, and R.sup.b is
as previously described. In a particular embodiment, R.sup.b is H.
In another particular embodiment, R.sup.b is --CH.sub.3,
--CH.sub.2--CH.sub.3, or --CH(CH.sub.3).sub.2.
[0287] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein L.sub.2 is --C(.dbd.O)NR.sup.c--, and
R.sup.c is as previously described. In a particular embodiment,
R.sup.c is H. In another particular embodiment, R.sup.c is
--CH.sub.3, --CH.sub.2--CH.sub.3, or --CH(CH.sub.3).sub.2.
[0288] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein L.sub.2 is --NR.sup.dC(.dbd.O)--, and
R.sup.d is as previously described. In a particular embodiment,
R.sup.d is H. In another particular embodiment, R.sup.d is
--CH.sub.3, --CH.sub.2--CH.sub.3, or --CH(CH.sub.3).sub.2.
[0289] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein L.sub.2 is --NR.sup.jC(.dbd.O)O--, and
R.sup.j is as previously described. In a particular embodiment,
R.sup.j is H. In another particular embodiment, R.sup.j is
--CH.sub.3, --CH.sub.2--CH.sub.3, or --CH(CH.sub.3).sub.2.
[0290] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein L.sub.2 is --SO.sub.2NR.sup.e--, and
R.sup.e is as previously described. In a particular embodiment,
R.sup.e is H. In another particular embodiment, R.sup.e is
--CH.sub.3, --CH.sub.2--CH.sub.3, or --CH(CH.sub.3).sub.2.
[0291] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein L.sub.2 is --NR.sup.fSO.sub.2--, and
R.sup.f is as previously described. In a particular embodiment,
R.sup.f is H. In another particular embodiment, R.sup.f is
--CH.sub.3, --CH.sub.2--CH.sub.3, or --CH(CH.sub.3).sub.2.
[0292] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is H, or CN.
[0293] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is C.sub.1-4 alkyl. In a
particular embodiment, G.sub.1 is --CH.sub.3, or
--CH.sub.2--CH.sub.3.
[0294] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is C.sub.1-4 alkyl substituted
with --CN, OH, halo or phenyl. In a particular embodiment, G.sub.1
is --CH.sub.3, --CH.sub.2--CH.sub.3, or --CH(CH.sub.3).sub.2, each
of which is substituted with --CN, OH, halo or phenyl. In a more
particular embodiment, G.sub.1 is --CF.sub.3, --CH.sub.2--Cl,
--CH.sub.2--CN, --CH.sub.2--OH or --CH.sub.2-Ph.
[0295] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is C.sub.3-7 cycloalkyl. In a
particular embodiment, G.sub.1 is cyclopropyl, cyclobutyl,
cyclopropyl, or cyclohexyl.
[0296] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is C.sub.3-7 cycloalkyl
substituted with --NH.sub.2. In a particular embodiment, G.sub.1 is
cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl, each of which
is substituted with --NH.sub.2.
[0297] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is 5-6 membered
heterocycloalkenyl containing 1 double bond, containing one to
three heteroatoms independently selected from O, N, and S. In a
particular embodiment, G.sub.1 is dihydrofuranyl, dihydrothiazolyl,
dihydrooxazolyl, dihydropyranyl, or dihydrothiopyranyl.
[0298] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is 5-6 membered
heterocycloalkenyl containing 1 double bond, containing one to
three heteroatoms independently selected from O, N, and S,
substituted with one or more independently selected R.sup.9, and
R.sup.9 is as previously defined. In another embodiment, G.sub.1 is
5-6 membered heterocycloalkenyl containing 1 double bond,
containing one to three heteroatoms independently selected from O,
N, and S, substituted with one or two independently selected
R.sup.9, and R.sup.9 is as previously defined. In a particular
embodiment, G.sub.1 is dihydrofuranyl, dihydrothiazolyl,
dihydrooxazolyl, dihydropyranyl, or dihydrothiopyranyl, each of
which is substituted with one or two independently selected
R.sup.9, and R.sup.9 is as previously defined.
[0299] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is 4-10 membered mono, bi or
spirocyclic heterocycloalkyl containing one to three heteroatoms
independently selected from O, N, and S. In a particular
embodiment, G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, thiomorpholinyl, or 2,6-diaza-spiro[3.3]heptane.
[0300] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is 4-10 membered mono, bi or
spirocyclic heterocycloalkyl containing one to three heteroatoms
independently selected from O, N, and S, substituted with one or
more independently selected R.sup.9, and R.sup.9 is as previously
defined. In another embodiment, G.sub.1 is 4-10 membered mono, bi
or spirocyclic heterocycloalkyl containing one to three heteroatoms
independently selected from O, N, and S, substituted with one or
two independently selected R.sup.9, and R.sup.9 is as previously
defined. In a particular embodiment, G.sub.1 is oxetanyl,
azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,
piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or
2,6-diaza-spiro[3.3]heptanes, each of which is substituted with one
or two independently selected R.sup.9, and R.sup.9 is as previously
defined.
[0301] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein R.sup.9 is oxo.
[0302] In another embodiment, a compound of the invention is
according to Formula I-IVd, wherein R.sup.9 is R.sup.10.
[0303] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein R.sup.10 is selected from OH, F, Cl, and
--CN.
[0304] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein R.sup.10 is C.sub.1-4 alkyl. In a
particular embodiment, R.sup.10 is selected from --CH.sub.3,
--CH.sub.2--CH.sub.3, and --CH(CH.sub.3).sub.2. In a more
particular embodiment, R.sup.10 is selected from --CH.sub.3, and
--CH.sub.2--CH.sub.3.
[0305] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein R.sup.10 is C.sub.1-4 alkyl substituted
with one or more independently selected OH, halo, or phenyl. In a
further embodiment, R.sup.10 is C.sub.1-4 alkyl substituted with
one to three independently selected OH, halo, or phenyl. In a more
particular embodiment, R.sup.10 is --CH.sub.3,
--CH.sub.2--CH.sub.3, or --CH(CH.sub.3).sub.2, each of which is
substituted with one to three independently selected OH, halo, or
phenyl. In a most particular embodiment, R.sup.10 is --CF.sub.3,
--CH.sub.2--CH.sub.2--OH, or --CH.sub.2-phenyl.
[0306] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein R.sup.10 is C.sub.1-4 alkoxy. In a
particular embodiment, R.sup.10 is selected from --OCH.sub.3,
--OCH.sub.2--CH.sub.3, and --OC(CH.sub.3).sub.3. In a particular
embodiment, R.sup.10 is --OCH.sub.3.
[0307] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein R.sup.10 is selected from
--SO.sub.2CH.sub.3, --C(.dbd.O)C.sub.1-4 alkoxy, and
--C(.dbd.O)C.sub.1-4 alkyl. In a particular embodiment, R.sup.10 is
selected from --SO.sub.2CH.sub.3, --C(.dbd.O)OCH.sub.3,
--C(.dbd.O)OCH.sub.2CH.sub.3, --C(.dbd.O)OCH(CH.sub.3).sub.2,
--C(.dbd.O)CH.sub.3, --C(.dbd.O)CH.sub.2CH.sub.3, and
--C(.dbd.O)OCH(CH.sub.3).sub.2. In a most particular embodiment,
R.sup.10 is selected from --SO.sub.2CH.sub.3, --C(.dbd.O)OCH.sub.3,
and --C(.dbd.O)CH.sub.3.
[0308] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein R.sup.10 is --NR.sup.gC(.dbd.O)C.sub.1-4
alkyl, and R.sup.g is as described previously. In a particular
embodiment, R.sup.10 is --NR.sup.gC(.dbd.O)CH.sub.3, or
--NR.sup.gC(.dbd.O)CH.sub.2CH.sub.3, and R.sup.g is as described
previously. In a more particular embodiment, R.sup.10 is
--NR.sup.gC(.dbd.O)CH.sub.3, or
--NR.sup.gC(.dbd.O)CH.sub.2CH.sub.3, and R.sup.g is H, --CH.sub.3,
or --CH.sub.2CH.sub.3. In a most particular embodiment, R.sup.10 is
--NHC(.dbd.O)CH.sub.3, or --NHC(.dbd.O)CH.sub.2CH.sub.3.
[0309] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected selected
from O, N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, and R.sup.9 is oxo. In a
further particular embodiment, G.sub.1 is oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, or
2,6-diaza-spiro[3.3]heptane, each of which is substituted with one
or two independently selected R.sup.9 groups, and R.sup.9 is
oxo.
[0310] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a further embodiment,
G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, or 2,6-diaza-spiro[3.3]heptane, each of which is
substituted with one or two independently selected R.sup.9 groups,
R.sup.9 is R.sup.10, and R.sup.10 is as previously described. In a
particular embodiment, R.sup.10 is selected from OH, F, Cl, and
--CN.
[0311] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a further embodiment,
G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, or 2,6-diaza-spiro[3.3]heptane, each of which is
substituted with one or two independently selected R.sup.9 groups,
R.sup.9 is R.sup.10, and R.sup.10 is as previously described. In a
particular embodiment, R.sup.10 is selected C.sub.1-4 alkyl. In a
more particular embodiment, R.sup.10 is selected from --CH.sub.3,
--CH.sub.2--CH.sub.3, and --CH(CH.sub.3).sub.2. In a most
particular embodiment, R.sup.10 is selected from --CH.sub.3, and
--CH.sub.2--CH.sub.3.
[0312] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a further embodiment,
G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, or 2,6-Diaza-spiro[3.3]heptane, each of which is
substituted with one or two independently selected R.sup.9 groups,
R.sup.9 is R.sup.10, and R.sup.10 is as previously described. In a
particular embodiment, R.sup.10 is C.sub.1-4 alkyl substituted with
one or more independently selected OH, halo, or phenyl. In a
further embodiment, R.sup.10 is C.sub.1-4 alkyl substituted with
one to three independently selected OH, halo, or phenyl. In a more
particular embodiment, R.sup.10 is --CH.sub.3,
--CH.sub.2--CH.sub.3, or --CH(CH.sub.3).sub.2, each of which is
substituted with one to three independently selected OH, halo, or
phenyl. In a most particular embodiment, R.sup.10 is --CF.sub.3,
--CH.sub.2--CH.sub.2--OH, or --CH.sub.2-phenyl.
[0313] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a further embodiment,
G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, or 2,6-diaza-spiro[3.3]heptane, each of which is
substituted with one or two independently selected R.sup.9 groups,
R.sup.9 is R.sup.10, and R.sup.10 is as previously described. In a
particular embodiment, R.sup.10 is C.sub.1-4 alkoxy. In a more
particular embodiment, R.sup.10 is selected from --OCH.sub.3,
--OCH.sub.2--CH.sub.3, and --OC(CH.sub.3).sub.3. In a most
particular embodiment, R.sup.10 is --OCH.sub.3.
[0314] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a further embodiment,
G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, or 2,6-Diaza-spiro[3.3]heptane, each of which is
substituted with one or two independently selected R.sup.9 groups,
R.sup.9 is R.sup.10, and R.sup.10 is as previously described. In a
particular embodiment, R.sup.10 is selected from
--SO.sub.2CH.sub.3, --C(.dbd.O)C.sub.1-4 alkoxy, and
--C(.dbd.O)C.sub.1-4 alkyl. In a more particular embodiment,
R.sup.10 is selected from --SO.sub.2CH.sub.3, --C(.dbd.O)OCH.sub.3,
--C(.dbd.O)OCH.sub.2CH.sub.3, --C(.dbd.O)OCH(CH.sub.3).sub.2,
--C(.dbd.O)CH.sub.3, --C(.dbd.O)CH.sub.2CH.sub.3, and
--C(.dbd.O)OCH(CH.sub.3).sub.2. In a most particular embodiment,
R.sup.10 is selected from --SO.sub.2CH.sub.3, --C(.dbd.O)OCH.sub.3,
and --C(.dbd.O)CH.sub.3.
[0315] In one embodiment, a compound of the invention is according
to Formula I-IVd, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a further embodiment,
G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, or 2,6-Diaza-spiro[3.3]heptane, each of which is
substituted with one or two independently selected R.sup.9 groups,
R.sup.9 is R.sup.10, and R.sup.10 is as previously described. In a
particular embodiment, R.sup.10 is --NR.sup.gC(.dbd.O)C.sub.1-4
alkyl, and R.sup.g is as described previously. In a particular
embodiment, R.sup.10 is --NR.sup.gC(.dbd.O)CH.sub.3, or
--NR.sup.gC(.dbd.O)CH.sub.2CH.sub.3, and R.sup.g is as described
previously. In a more particular embodiment, R.sup.10 is
--NR.sup.gC(.dbd.O)CH.sub.3, or
--NR.sup.gC(.dbd.O)CH.sub.2CH.sub.3, and R.sup.g is H, --CH.sub.3,
or --CH.sub.2CH.sub.3. In a most particular embodiment, R.sup.10 is
--NHC(.dbd.O)CH.sub.3, or --NHC(.dbd.O)CH.sub.2CH.sub.3.
[0316] In one embodiment, a compound of the invention is according
to Formula Va, Vb, Vc, or Vd:
##STR00010##
[0317] wherein Y, Z, R.sup.6, W.sub.1, and G.sub.1 are as described
above.
[0318] In one embodiment, a compound of the invention is according
to Formula Va-Vd, wherein W.sub.1 is C.sub.1-4 alkylene. In a
particular embodiment, W.sub.1 is --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --C(CH.sub.3)H--,
--CH.sub.2--CH.sub.2--CH.sub.2-- or --CH.sub.2--C(CH.sub.3)H--. In
a more particular embodiment, W.sub.1 is --CH.sub.2--, or
--C(CH.sub.3)H--. In a most particular embodiment, W.sub.1 is
--CH.sub.2--.
[0319] In one embodiment, a compound of the invention is according
to Formula VIa, VIb, VIc, or VId:
##STR00011##
[0320] wherein Y, Z, R.sup.6, and G.sub.1 are as described
above.
[0321] In one embodiment, a compound of the invention is according
to Formula Va-VId, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected selected
from O, N, and S. In a particular embodiment, G.sub.1 is oxetanyl,
azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,
piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In a
more particular embodiment, G.sub.1 is azetidinyl.
[0322] In one embodiment, a compound of the invention is according
to Formula Va-VId, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, which heterocycle is substituted with one or more
independently selected R.sup.9 groups. In a further embodiment,
G.sub.1 is 4-7 membered heterocycloalkyl containing one or more
heteroatoms independently selected from O, N, and S, which
heterocycle is substituted with one or two independently selected
R.sup.9 groups. In a particular embodiment, G.sub.1 is oxetanyl,
azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,
piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of
which is substituted with one or two independently selected R.sup.9
groups. In a more particular embodiment, G.sub.1 is azetidinyl
substituted with one or two independently selected R.sup.9
groups.
[0323] In one embodiment, a compound of the invention is according
to Formula Va-VId, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, and R.sup.9 is oxo. In a
further particular embodiment, G.sub.1 is oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, or thiomorpholinyl, each of which is
substituted with one or two independently selected R.sup.9 groups,
and R.sup.9 is oxo.
[0324] In one embodiment, a compound of the invention is according
to Formula Va-VId, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected selected
from O, N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a further embodiment,
G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or
thiomorpholinyl, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a particular embodiment,
R.sup.10 is selected from OH, F, Cl, and --CN. In a more particular
embodiment, G.sub.1 is azetidinyl substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a most particular
embodiment, R.sup.10 is selected from OH, F, Cl, and --CN.
[0325] In one embodiment, a compound of the invention is according
to Formula Va-VId, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a further embodiment,
G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or
thiomorpholinyl, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a particular embodiment,
R.sup.10 is selected C.sub.1-4 alkyl. In a more particular
embodiment, R.sup.10 is selected from --CH.sub.3,
--CH.sub.2--CH.sub.3, and --CH(CH.sub.3).sub.2. In a most
particular embodiment, R.sup.10 is selected from --CH.sub.3, and
--CH.sub.2--CH.sub.3.
[0326] In one embodiment, a compound of the invention is according
to Formula Va-VId, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a further embodiment,
G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or
thiomorpholinyl, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a particular embodiment,
R.sup.10 is C.sub.1-4 alkyl substituted with one or more
independently selected OH, halo, phenyl. In a further embodiment,
R.sup.10 is C.sub.1-4 alkyl substituted with one to three
independently selected OH, halo, and phenyl. In a more particular
embodiment, R.sup.10 is --CH.sub.3, --CH.sub.2--CH.sub.3, and
--CH(CH.sub.3).sub.2, each of which is substituted with one to
three independently selected OH, halo, and phenyl. In a most
particular embodiment, R.sup.10 is --CF.sub.3,
--CH.sub.2--CH.sub.2--OH, and --CH.sub.2-phenyl.
[0327] In one embodiment, a compound of the invention is according
to Formula Va-VId, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a further embodiment,
G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or
thiomorpholinyl, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a particular embodiment,
R.sup.10 is C.sub.1-4 alkoxy. In a more particular embodiment,
R.sup.10 is selected from --OCH.sub.3, --OCH.sub.2--CH.sub.3, and
--OC(CH.sub.3).sub.3. In a most particular embodiment, R.sup.10 is
--OCH.sub.3.
[0328] In one embodiment, a compound of the invention is according
to Formula Va-VId, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a further embodiment,
G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or
thiomorpholinyl, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a particular embodiment,
R.sup.10 is selected from --SO.sub.2CH.sub.3, --C(.dbd.O)C.sub.1-4
alkoxy, and --C(.dbd.O)C.sub.1-4 alkyl. In a more particular
embodiment, R.sup.10 is selected from --SO.sub.2CH.sub.3,
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)OCH.sub.2CH.sub.3,
--C(.dbd.O)OCH(CH.sub.3).sub.2, --C(.dbd.O)CH.sub.3,
--C(.dbd.O)CH.sub.2CH.sub.3, and --C(.dbd.O)OCH(CH.sub.3).sub.2. In
a most particular embodiment, R.sup.10 is selected from
--SO.sub.2CH.sub.3, --C(.dbd.O)OCH.sub.3, and
--C(.dbd.O)CH.sub.3.
[0329] In one embodiment, a compound of the invention is according
to Formula Va-VId, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a further embodiment,
G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or
thiomorpholinyl, each of which is substituted with one or two
independently selected R.sup.9 groups, R.sup.9 is R.sup.10, and
R.sup.10 is as previously described. In a particular embodiment,
R.sup.10 is --NR.sup.gC(.dbd.O)C.sub.1-4 alkyl, and R.sup.g is as
described previously. In a particular embodiment, R.sup.10 is
--NR.sup.gC(.dbd.O)CH.sub.3, or
--NR.sup.gC(.dbd.O)CH.sub.2CH.sub.3, and R.sup.g is as described
previously. In a more particular embodiment, R.sup.10 is
--NR.sup.gC(.dbd.O)CH.sub.3, or
--NR.sup.gC(.dbd.O)CH.sub.2CH.sub.3, and R.sup.g is H, --CH.sub.3,
or --CH.sub.2CH.sub.3. In a most particular embodiment, R.sup.10 is
--NHC(.dbd.O)CH.sub.3, or --NHC(.dbd.O)CH.sub.2CH.sub.3.
[0330] In one embodiment, a compound of the invention is according
to Formula I-VId, wherein R.sup.6 is H, --CH.sub.3 or halo. In a
particular embodiment, R.sup.6 is H, --CH.sub.3, F, or Cl. In a
more particular embodiment, R.sup.6 is H, --CH.sub.3, or F. In a
more particular embodiment, R.sup.6 is H.
[0331] In one embodiment, a compound of the invention is according
to Formula I-VId, wherein Y is N and Z is CH.
[0332] In one embodiment, a compound of the invention is according
to Formula I-VId, wherein Y is CH and Z is N.
[0333] In one embodiment, a compound of the invention according to
Formula I is selected from: [0334]
2-((2-ethyl-6-(piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-
-(4-fluorophenyl)thiazole-5-carbonitrile, [0335]
2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)im-
idazo[1,2-a]pyrazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0336]
2-((6-(4-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-ethy-
limidazo[1,2-a]pyrazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0337]
2-((6-(4-(2-(azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-ethylimidazo[1,2-
-a]pyrazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0338]
2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2--
ethylimidazo[1,2-a]pyrazin-6-yl)
piperazin-1-yl)-N,N-dimethylacetamide, [0339]
(R)-2-((2-ethyl-6-(4-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)pipe-
razin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thi-
azole-5-carbonitrile, [0340]
(S)-2-((2-ethyl-6-(4-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperazin-1-
-yl)imidazo[1,2-a]pyrazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0341]
2-((2-ethyl-6-(4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)imidazo[1-
,2-a]pyrazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0342]
2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylim-
idazo[1,2-a]pyrazin-6-yl) piperazin-1-yl)-N-methylacetamide, [0343]
2-((2-ethyl-6-(4-(2-morpholino-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]py-
razin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0344]
2-((2-ethyl-6-(4-(2-(3-fluoroazetidin-1-yl)-2-oxoethyl)piperazin-1-
-yl)imidazo[1,2-a]pyrazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0345]
2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)acetoyl)piperazin-1-yl)imidaz-
o[1,2-a]pyrazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0346]
1-(azetidin-1-yl)-2-(4-(2-ethyl-3-((4-fluorophenyl)thiazol-2-yl)(methyl)a-
mino)imidazo[1,2-a]pyrazin-6-yl)piperazin-1-yl)ethanone, [0347]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-a]pyrazin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,
[0348]
2-(2-((2-ethyl-6-(piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methy-
l)amino)thiazol-4-yl)-5-fluorobenzonitrile, [0349]
2-(2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl-
)imidazo[1,2-a]pyrazin-3-yl)
(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile, [0350]
2-(6-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl-
)imidazo[1,2-a]pyrazin-3-yl)
(methyl)amino)pyridin-2-yl)-5-fluorobenzonitrile, [0351]
2-(2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl-
)imidazo[1,2-a]pyrazin-3-yl)
(methyl)amino)pyrimidin-4-yl)-5-fluorobenzonitrile, [0352]
2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)im-
idazo[1,2-a]pyrazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)pyrimidine-5-carbonitrile, [0353]
2-((2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[-
1,2-a]pyrazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0354]
2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-1,2,3,6-tetrahyd-
ropyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-(4-fluorophenyl-
)thiazole-5-carbonitrile, [0355]
2-((2-ethyl-6-(piperidin-4-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-
-(4-fluorophenyl)thiazole-5-carbonitrile, [0356]
2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)im-
idazo[1,2-a]pyrazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0357]
(R)-2-((2-ethyl-6-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperidin-4-
-yl)imidazo[1,2-a]pyrazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0358]
(S)-2-((2-ethyl-6-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperidin-4-
-yl)imidazo[1,2-a]pyrazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0359]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)
piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone, [0360]
2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin--
1-yl)imidazo[1,2-b]pyridazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0361]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)
piperazin-1-yl)-1-(2-methylpyrrolidin-1-yl)ethanone, [0362]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imi-
dazo[1,2-b]pyridazin-6-yl)
piperazin-1-yl)-1-(2-(hydroxymethyl)pyrrolidin-1-yl)ethanone,
[0363]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperazin-1-yl)-N-methylacetamide, [0364]
1-(3,3-difluoropyrrolidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiaz-
ol-2-yl)
(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethanon-
e, [0365]
1-(2,5-dimethylpyrrolidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophe-
nyl)thiazol-2-yl)
(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethanone,
[0366]
(R)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino-
)imidazo[1,2-b]pyridazin-6-yl)
piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone, [0367]
(S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidaz-
o[1,2-b]pyridazin-6-yl)
piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone, [0368]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperazin-1-yl)-N-(2-hydroxyethyl)acetamide,
[0369]
1-(azetidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methy-
l)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethanone,
[0370]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperazin-1-yl)-N-isopropyl-N-methylacetamide,
[0371]
N-(2-ethyl-6-(4-(oxetan-3-yl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-
-4-(4-fluorophenyl)-N-methylthiazol-2-amine, [0372]
N-(2-ethyl-6-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)imidazo[1,2-b]py-
ridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine, [0373]
5-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl) piperazin-1-yl)methyl)oxazolidin-2-one, [0374]
5-((4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(meth-
yl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)methyl)oxazolidin-2-o-
ne, [0375]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-
imidazo[1,2-b]pyridazin-6-yl)
piperazin-1-yl)-N,N-dimethylacetamide, [0376]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl-
)(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N,N-dimethylac-
etamide, [0377]
2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylim-
idazo[1,2-b]pyridazin-6-yl) piperazin-1-yl)-N,N-dimethylacetamide,
[0378]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(2,2,2-trifluoroacetoyl)thiazol-2--
yl)
(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N,N-dimethy-
lacetamide, [0379]
1-(2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo-
[1,2-b]pyridazin-6-yl) piperazin-1-yl)ethyl)pyrrolidin-2-one,
[0380]
(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone,
[0381]
N-(2-ethyl-6-(4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)imidazo[1,2--
b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
[0382]
3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperazin-1-yl)propan-1-ol, [0383]
3-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methy-
l)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)propan-1-ol,
[0384]
3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperazin-1-yl)propanenitrile, [0385]
3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperazin-1-yl)propanamide, [0386]
N-(2-ethyl-6-(4-(2-methoxyethyl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3--
yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine, [0387]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperazin-1-yl)-N-isopropylacetamide, [0388]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone,
[0389] tert-butyl
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperazin-1-yl)ethylcarbamate, [0390]
N-(2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo-
[1,2-b]pyridazin-6-yl) piperazin-1-yl)ethyl)acetamide, [0391] ethyl
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperazin-1-yl)ethylcarbamate, [0392]
(S)-tert-butyl
4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylate, [0393]
(S)-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[-
1,2-b]pyridazin-6-yl) piperazin-2-yl)methanol, [0394]
(S)-7-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl) tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one,
[0395]
(S)--N-(2-ethyl-6-(3-(methoxymethyl)-4-(methylsulfonyl)piperazin-1-yl)imi-
dazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
[0396]
(S)-(1-(3-(dimethylamino)propylsulfonyl)-4-(2-ethyl-3-((4-(4-fluor-
ophenyl)thiazol-2-yl)
(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)piperazin-2-yl)methanol,
[0397]
(S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino-
)imidazo[1,2-b]pyridazin-6-yl)-2-(hydroxymethyl)
piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone, [0398]
(S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidaz-
o[1,2-b]pyridazin-6-yl)-2-(hydroxymethyl)
piperazin-1-yl)-1-morpholinoethanone, [0399]
(S)-8-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl) hexahydropyrazino[2,1-c][1,4]oxazin-4(1H)-one,
[0400]
(S)-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[-
1,2-b]pyridazin-6-yl)-1-(methylsulfonyl) piperazin-2-yl)methanol,
[0401]
(S)-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(met-
hyl)amino)imidazo[1,2-b]pyridazin-6-yl)-1-(methylsulfonyl)piperazin-2-yl)m-
ethanol, [0402]
(R)-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[-
1,2-b]pyridazin-6-yl)-1-(methylsulfonyl) piperazin-2-yl)methanol,
[0403]
3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)
piperazin-1-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one, [0404]
N-(2-ethyl-6-(4-(ethylsulfonyl)piperazin-1-yl)imidazo[1,2-b]pyrida-
zin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine, [0405]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)-1-(methylsulfonyl) piperazin-2-ethanol, [0406]
2-(4-(2-ethyl-3-((4-(4-fluoro-2-methylphenyl)thiazol-2-yl)(methyl)amino)i-
midazo[1,2-b]pyridazin-6-yl) piperazin-1-yl)-N,N-dimethylacetamide,
[0407]
tert-butyl-(1R,4S)-5-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)-
amino)imidazo[1,2-b]pyridazin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbo-
xylate, [0408]
1-((1R,4S)-5-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)im-
idazo[1,2-b]pyridazin-6-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethanone,
[0409]
N-(2-ethyl-6-((1S,4R)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]he-
ptan-2-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-
-2-amine, [0410]
N-(2-ethyl-6-(3-azaspiro[5.5]undecan-3-yl)imidazo[1,2-b]pyridazin-3-yl)-4-
-(4-fluorophenyl)-N-methylthiazol-2-amine, [0411]
N-(2-ethyl-6-morpholinoimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-
-methylthiazol-2-amine, [0412]
6-(1,1-Dioxo-thiomorpholin-4-yl)-2-ethyl-imidazo[1,2-b]pyridazin-3-yl]-[4-
-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine, [0413]
N-(6-(4-(dimethylamino)piperidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-y-
l)-4-(4-fluorophenyl)-N-methylthiazol-2-amine, [0414] tert-butyl
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl) piperidin-4-ylcarbamate, [0415]
N-(6-(4-aminopiperidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fl-
uorophenyl)-N-methylthiazol-2-amine, [0416]
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperidin-4-yl)methanesulfonamide, [0417]
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)
piperidin-4-yl)tetrahydro-2H-pyran-4-carboxamide, [0418]
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imi-
dazo[1,2-b]pyridazin-6-yl) piperidin-4-yl)-2-hydroxyacetamide,
[0419]
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperidin-4-yl)-3-methyloxetane-3-carboxamide,
[0420] tert-butyl
4-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)
piperidin-4-ylcarbamoyl)piperidine-1-carboxylate, [0421]
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imi-
dazo[1,2-b]pyridazin-6-yl) piperidin-4-yl)piperidine-4-carboxamide,
[0422]
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperidin-4-yl)pyrrolidine-1-carboxamide,
[0423]
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)piperidin-4-ol, [0424]
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)piperidin-3-ol, [0425]
N-ethyl-2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)im-
idazo[1,2-b]pyridazin-6-yl) piperidin-3-yloxy)acetamide, [0426]
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)piperidin-4-yl)methanol, [0427]
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)piperidin-3-yl)methanol, [0428]
1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,-
2-b]pyridazin-6-yl)-piperidine-4-carboxylic acid ethyl ester,
[0429]
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)piperidine-4-carboxylic acid, [0430]
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)-N-(2-hydroxyethyl) piperidine-4-carboxamide,
[0431]
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)piperidine-4-carboxamide, [0432]
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)piperidine-3-carboxamide, [0433]
[1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1-
,2-b]pyridazin-6-yl)-piperidin-3-ylmethyl]-carbamic acid tert-butyl
ester, [0434]
N-(6-(3-(aminomethyl)piperidin-1-yl)-2-ethylimidazo[1,2-b]pyridazi-
n-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine, [0435]
N-((1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl) piperidin-3-yl)methyl)methanesulfonamide,
[0436]
[1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1-
,2-b]pyridazin-6-yl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl
ester,
[0437]
N-(6-(4-(aminomethyl)piperidin-1-yl)-2-ethylimidazo[1,2-b]pyridazi-
n-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine, [0438]
N-((1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl) piperidin-4-yl)methyl)methanesulfonamide,
[0439]
3-((1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl) piperidin-4-yl)methyl)-1,1-dimethylurea,
[0440]
N-((1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl)
piperidin-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamide, [0441]
2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) piperidin-4-yl)-N,N-dimethylacetamide, [0442]
N-(2-ethyl-6-(4-morpholinopiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4--
(4-fluorophenyl)-N-methylthiazol-2-amine, [0443]
N-(2-ethyl-6-(3-morpholinopiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4--
(4-fluorophenyl)-N-methylthiazol-2-amine, [0444]
N-(6-(1,4'-bipiperidin-1'-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-f-
luorophenyl)-N-methylthiazol-2-amine, [0445]
1'-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)-1,3'-bipiperidin-4-ol, [0446]
N-(2-ethyl-6-(4-phenylpiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-f-
luorophenyl)-N-methylthiazol-2-amine, [0447]
N-cyclopropyl-1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino-
)imidazo[1,2-b]pyridazin-6-yl)piperidine-4-sulfonamide, [0448]
1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)-1,4-diazepan-1-yl)ethanone, [0449]
N-(2-ethyl-6-(4-(methylsulfonyl)-1,4-diazepan-1-yl)imidazo[1,2-b]pyridazi-
n-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine, [0450]
N-(2-ethyl-6-(8-oxa-2-azaspiro[4.5]decan-2-yl)imidazo[1,2-b]pyridazin-3-y-
l)-4-(4-fluorophenyl)-N-methylthiazol-2-amine, [0451]
7-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)-1-oxa-3,7-diazaspiro [4.4]nonan-2-one, [0452]
7-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)-3-methyl-1-oxa-3,7-diazaspiro[4.4]nonan-2-one,
[0453]
7-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)a-
mino)imidazo[1,2-b]pyridazin-6-yl)-3-methyl-1-oxa-3,7-diazaspiro[4.4]nonan-
-2-one, [0454]
7-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)-2,7-diazaspiro [4.4]nonane-1,3-dione, [0455]
tert-butyl
5-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl) hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate,
[0456]
N-(2-ethyl-6-(5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)im-
idazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
[0457]
1-(5-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imi-
dazo[1,2-b]pyridazin-6-yl)
hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethanone, [0458]
N-(6-(5-(3-chloropropylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-
-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-a-
mine, [0459]
N-(6-(5-(3-(dimethylamino)propylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(-
1H)-yl)-2-ethylimidazo
[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
[0460]
N-(2-ethyl-6-(5-(3-morpholinopropylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-
-2(1H)-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-
-2-amine, [0461]
(S)-1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl) pyrrolidine-3-carbonitrile, [0462]
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)pyrrolidin-3-ol, [0463]
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)pyrrolidin-3-yl formate, [0464]
N-(2-ethyl-6-(3-thiomorpholinopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-y-
l)-4-(4-fluorophenyl)-N-methylthiazol-2-amine, [0465]
1-(3-((5-chloro-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimid-
azo[1,2-b]pyridazin-6-yl) pyrrolidin-3-one, [0466] tert-butyl
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl) pyrrolidin-3-ylcarbamate, [0467]
N-(6-(3-aminopyrrolidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-f-
luorophenyl)-N-methylthiazol-2-amine, [0468] methyl
2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) pyrrolidin-3-ylamino)acetate, [0469]
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) pyrrolidin-3-yl)-2-hydroxyacetamide, [0470]
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) pyrrolidin-3-yl)methanesulfonamide, [0471]
(S)-1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl) pyrrolidine-2-carboxylic acid, [0472]
1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,-
2-b]pyridazin-6-yl)-pyrrolidine-3-carboxylic acid methyl ester,
[0473]
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)-N-(2-hydroxyethyl) pyrrolidine-3-carboxamide,
[0474]
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl) pyrrolidin-3-yl)(morpholino)methanone, [0475]
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl) pyrrolidin-2-yl)methanol, [0476]
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl) pyrrolidin-3-yl)methanol, [0477]
(1-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)-
amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)methanol, [0478]
3-(4-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo-
[1,2-b]pyridazin-6-yl) pyrrolidin-3-yl)piperazin-1-yl)propan-1-ol,
[0479]
4-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) pyrrolidin-3-yl)piperazin-2-one, [0480]
N-(2-ethyl-6-(3-morpholinopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-
-(4-fluorophenyl)-N-methylthiazol-2-amine, [0481]
(2-((2-ethyl-6-(3-morpholinopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-
(methyl)amino)-4-(4-fluorophenyl) thiazol-5-yl)methanol, [0482]
2-((2-ethyl-6-(3-morpholinopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(-
methyl)amino)-4-(4-fluorophenyl) thiazole-5-carbonitrile, [0483]
{6-[3-(1,1-Dioxo-thiomorpholin-4-yl)-pyrrolidin-1-yl]-2-ethyl-imidazo[1,2-
-b]pyridazin-3-yl}-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine,
[0484]
N-(2-ethyl-6-(3-(piperidin-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-
-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine, [0485]
1-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) pyrrolidin-3-yl)piperidin-4-ol, [0486]
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)azetidin-3-yl)methanol, [0487]
[1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1-
,2-b]pyridazin-6-yl)-azetidin-3-yl]-carbamic acid tert-butyl ester,
[0488]
2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)
azetidin-3-ylamino)-1-(3-hydroxyazetidin-1-yl)ethanone, [0489]
2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) azetidin-3-ylamino)-N,N-dimethylacetamide,
[0490]
2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) azetidin-3-ylamino)-N-methylacetamide, [0491]
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl) azetidin-3-yl)methanesulfonamide, [0492]
(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2--
b]pyridazin-6-yl)azetidin-3-yl)(3-hydroxypyrrolidin-1-yl)methanone,
[0493]
2-((2-ethyl-6-(4-((2-oxooxazolidin-5-yl)methyl)piperazin-1-yl)imidazo[1,2-
-b]pyridazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0494]
(S)-2-((2-ethyl-6-(3-(hydroxymethyl)-4-(methylsulfonyl)piperazin-1-yl)imi-
dazo[1,2-b]pyridazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0495]
2-((2-ethyl-6-(2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-7-yl)imidazo[1,2-b]py-
ridazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0496]
2-((2-ethyl-6-(3-methyl-2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-7-yl)-
imidazo[1,2-b]pyridazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0497]
2-((2-ethyl-6-(3-methyl-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonan-7-yl)imidazo-
[1,2-b]pyridazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0498]
tert-butyl
7-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimida-
zo[1,2-b]pyridazin-6-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate,
[0499]
2-((2-ethyl-6-(2,7-diazaspiro[4.4]nonan-2-yl)imidazo[1,2-b]pyridazin-3-yl-
)(methyl)amino)-4-(4-fluorophenyl) thiazole-5-carbonitrile, [0500]
2-((6-(7-acetoyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-ethylimidazo[1,2-b]pyri-
dazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
[0501] methyl
(1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimid-
azo[1,2-b]pyridazin-6-yl)-3-hydroxypyrrolidin-3-yl), [0502]
N-((1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyli-
midazo[1,2-b]pyridazin-6-yl)-3-hydroxypyrrolidin-3-yl)methyl)acetamide,
[0503]
N-((1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-
-ethylimidazo[1,2-b]pyridazin-6-yl)-3-hydroxypyrrolidin-3-yl)methyl)isobut-
yramide, [0504]
2-((2-ethyl-6-(3-hydroxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(met-
hyl)amino)-4-(4-fluorophenyl) thiazole-5-carbonitrile, [0505]
2-((2-ethyl-6-(3-oxopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)-
amino)-4-(4-fluorophenyl) thiazole-5-carbonitrile, [0506]
2-((2-ethyl-6-(3-(hydroxymethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-
-yl)(methyl)amino)-4-(4-fluorophenyl) thiazole-5-carbonitrile,
[0507]
(S)-2-((2-ethyl-6-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethylamino)pyrrolid-
in-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thia-
zole-5-carbonitrile, [0508]
(S)-2-(1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-eth-
ylimidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylamino)-N,N-dimethylacetamide-
, [0509]
(R)-2-((2-ethyl-6-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethylamino)-
pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophe-
nyl)thiazole-5-carbonitrile, [0510]
(R)-2-(1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-eth-
ylimidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylamino)-N,N-dimethylacetamide-
, [0511]
2-((6-(3-((2S,6R)-2,6-dimethylmorpholino)pyrrolidin-1-yl)-2-ethyl-
imidazo[1,2-b]pyridazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0512]
2-((2-ethyl-6-(3-(4-(hydroxymethyl)piperidin-1-yl)pyrrolidin-1-yl)imidazo-
[1,2-b]pyridazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0513]
2-((6-(3-(4-acetoylpiperazin-1-yl)pyrrolidin-1-yl)-2-ethylimidazo[1,2-b]p-
yridazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0514]
N-(1-(1-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-
-2-ethylimidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)piperidin-4-yl)-N-met-
hylacetamide, [0515]
2-((2-ethyl-6-(3-(4-hydroxypiperidin-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]p-
yridazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0516]
2-((2-ethyl-6-(3-(4-methoxypiperidin-1-yl)pyrrolidin-1-yl)imidazo[-
1,2-b]pyridazin-3-yl)
(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0517]
2-((2-ethyl-6-((3S,4S)-3-hydroxy-4-morpholinopyrrolidin-1-yl)imidazo[1,2--
b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,
[0518]
1-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(m-
ethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ol, [0519]
(2-((2-ethyl-6-(8-oxa-2-azaspiro[4.5]decan-2-yl)imidazo[1,2-b]pyridazin-3-
-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)methanol, [0520]
[1-(3-{[5-Cyano
-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl
-imidazo[1,2-b]pyridazin-6-yl)-azetidin-3-yl]-carbamic acid
tert-butyl ester, [0521]
2-((6-(3-aminoazetidin-1-yl)-2-ethylimidazo[1,2-b]pyridazin-3-yl)(methyl)-
amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile, [0522]
2-((2-ethyl-6-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethylamino)azetidin-1-y-
l)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-
-carbonitrile, [0523]
N-(1-(3-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidaz-
o[1,2-b]pyridazin-6-yl)azetidin-3-yl)methanesulfonamide, [0524]
2-((2-ethyl-6-(3-(morpholine
-4-carbonyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(-
4-fluorophenyl)thiazole-5-carbonitrile, [0525]
2-((2-ethyl-6-(3-(3-hydroxypyrrolidine-1-carbonyl)azetidin-1-yl)imidazo[1-
,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitri-
le, [0526]
4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}--
imidazo[1,2-b]pyridazin-6-yl)-3,6-dihydro-2H-pyridine -1-carboxylic
acid tert-butyl ester, [0527]
N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1-
,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,
[0528]
(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)--
1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)methanol,
[0529]
2-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methyls-
ulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)aceto-
nitrile, [0530]
3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl-
)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propanamide, [0531]
3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl-
)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propanenitrile, [0532]
3-(3-((4-(4-fluorophenyl)-5-(2,2,2-trifluoroacetoyl)thiazol-2-yl)(methyl)-
amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)pr-
opanenitrile, [0533]
3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl-
)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propan-1-ol, [0534]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,
[0535]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imi-
dazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,
[0536]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methy-
l)amino)imidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide-
, [0537]
2-(2-((2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4--
yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzon-
itrile, [0538]
2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazi-
n-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile, [0539]
2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazi-
n-3-yl)(methyl)amino)-5-(hydroxymethyl)thiazol-4-yl)-5-fluorobenzonitrile,
[0540]
2-(2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperid-
in-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorob-
enzonitrile, [0541]
2-(4-(3-((4-(2-cyano-4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylim-
idazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,
[0542]
2-(4-(3-((4-(2-cyano-4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2--
ethylimidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N-methylacetamide,
[0543]
2-(2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperid-
in-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-5-methylthiazol-4-yl)--
5-fluorobenzonitrile, [0544]
2-(4-(3-((4-(2-cyano-4-fluorophenyl)-5-methylthiazol-2-yl)(methyl)amino)--
2-ethylimidazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-N-methylacetamide,
[0545]
2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin--
4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-
e-5-carbonitrile, [0546]
2-(6-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl-
)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)pyridin-2-yl)-5-fluorobenzonit-
rile, [0547]
2-(4-(2-ethyl-3-((6-(4-fluorophenyl)pyridin-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,
[0548]
2-(4-(2-ethyl-3-((4-(4-fluorophenyl)pyrimidin-2-yl)(methyl)amino)i-
midazo[1,2-b]pyridazin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)etha-
none, [0549]
2-(4-(2-ethyl-3-((2-(4-fluorophenyl)pyrimidin-4-yl)(methyl)amino)imidazo[-
1,2-b]pyridazin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,
[0550]
2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin--
4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-6-(4-fluorophenyl)nicotin-
onitrile, [0551]
6-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)im-
idazo[1,2-b]pyridazin-3-yl)(methyl)amino)-2-(4-fluorophenyl)nicotinonitril-
e, [0552]
2-(5-((2-ethyl-6-(piperidin-4-yl)imidazo[1,2-b]pyridazin-3-yl)(m-
ethyl)amino)-1,2,4-thiadiazol-3-yl)-5-fluorobenzonitrile, and
[0553]
2-(5-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl-
)imidazo[1,2-b]pyridazin-3-yl)(methyl)amino)-1,2,4-thiadiazol-3-yl)-5-fluo-
robenzonitrile.
[0554] In one embodiment a compound of the invention is not an
isotopic variant.
[0555] In one aspect a compound of the invention according to any
one of the embodiments herein described is present as the free
base.
[0556] In one aspect a compound of the invention according to any
one of the embodiments herein described is a pharmaceutically
acceptable salt.
[0557] In one aspect a compound of the invention according to any
one of the embodiments herein described is a solvate of the
compound.
[0558] In one aspect a compound of the invention according to any
one of the embodiments herein described is a solvate of a
pharmaceutically acceptable salt of a compound.
[0559] While specified groups for each embodiment have generally
been listed above separately, a compound of the invention includes
one in which several or each embodiment in the above Formula, as
well as other formulae presented herein, is selected from one or
more of particular members or groups designated respectively, for
each variable. Therefore, this invention is intended to include all
combinations of such embodiments within its scope.
[0560] While specified groups for each embodiment have generally
been listed above separately, a compound of the invention may be
one for which one or more variables (for example, R groups) is
selected from one or more embodiments according to any of the
Formula(e) listed above. Therefore, the present invention is
intended to include all combinations of variables from any of the
disclosed embodiments within its scope.
[0561] Alternatively, the exclusion of one or more of the specified
variables from a group or an embodiment, or combinations thereof is
also contemplated by the present invention.
[0562] In certain aspects, the present invention provides prodrugs
and derivatives of the compounds according to the formulae above.
Prodrugs are derivatives of the compounds of the invention, which
have metabolically cleavable groups and become by solvolysis or
under physiological conditions the compounds of the invention,
which are pharmaceutically active, in vivo. Such examples include,
but are not limited to, choline ester derivatives and the like,
N-alkylmorpholine esters and the like.
[0563] Other derivatives of the compounds of this invention have
activity in both their acid and acid derivative forms, but the acid
sensitive form often offers advantages of solubility, tissue
compatibility, or delayed release in the mammalian organism
(Bundgaard 1992). Prodrugs include acid derivatives well know to
practitioners of the art, such as, for example, esters prepared by
reaction of the parent acid with a suitable alcohol, or amides
prepared by reaction of the parent acid compound with a substituted
or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
Simple aliphatic or aromatic esters, amides and anhydrides derived
from acidic groups pendant on the compounds of this invention are
preferred prodrugs. In some cases it is desirable to prepare double
ester type prodrugs such as (acyloxy)alkyl esters or
((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the
C.sub.1 to C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, aryl,
C.sub.7-C.sub.12 substituted aryl, and C.sub.7-C.sub.12 arylalkyl
esters of the compounds of the invention.
CLAUSES
[0564] 1) A compound according to Formula I:
[0564] ##STR00012## [0565] wherein [0566] R.sup.1a is H, halo or
C.sub.1-4 alkyl; [0567] R.sup.1b is: [0568] halo, [0569] C.sub.1-4
alkyl (which alkyl is optionally substituted with one or more
independently selected halo), or [0570] C.sub.1-4 alkoxy (which
alkoxy is optionally substituted with one or more independently
selected halo); [0571] X is --S--, --O--, --N.dbd.CH--,
--CH.dbd.N-- or --CH.dbd.CH--; [0572] W is N, or CR.sup.3 [0573]
when W is N, R.sup.2 is: [0574] H, [0575] --CN, [0576] halo, [0577]
C.sub.1-4 alkyl (which alkyl is optionally substituted with one or
more independently selected OH, or CN), [0578] --C(.dbd.O)CH.sub.3,
[0579] --C(.dbd.O)CF.sub.3, [0580] --C(.dbd.O)OCH.sub.3, [0581]
--C(.dbd.O)NH.sub.2, [0582] --NHC(.dbd.O)CH.sub.3, or [0583] when W
is CR.sup.3, one of R.sup.2 or R.sup.3 is: [0584] H, [0585] --CN,
[0586] halo, [0587] C.sub.1-4 alkyl (which alkyl is optionally
substituted with one or more independently selected OH, or CN),
[0588] --C(.dbd.O)CH.sub.3, [0589] --C(.dbd.O)CF.sub.3, [0590]
--C(.dbd.O)OCH.sub.3, [0591] --C(.dbd.O)NH.sub.2, [0592]
--NHC(.dbd.O)CH.sub.3, [0593] and the other is H, or C.sub.1-4
alkyl; [0594] R.sup.4 is C.sub.1-4 alkyl; [0595] R.sup.5 is
C.sub.1-4 alkyl optionally substituted with one or more
independently selected CN, OH, halo, or --C(.dbd.O)NH.sub.2; [0596]
one of Y and Z is CH and the other is N; [0597] R.sup.6 is selected
from H, --CH.sub.3 and halo; [0598] Cy is: [0599] C.sub.4-10
cycloalkyl, [0600] 4-10 membered mono or bicyclic heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, or [0601] 4-7 membered heterocycloalkenyl containing 1
double bond, containing one or more heteroatoms independently
selected from O, N, and S; [0602] each R.sup.7 is independently
selected from: [0603] OH, [0604] oxo, [0605] halo, and [0606]
C.sub.1-4 alkyl (which alkyl is optionally substituted with one or
more independently selected OH, or C.sub.1-4 alkoxy); [0607] the
subscript a is 0, 1 or 2; [0608] R.sup.8 is
-(L.sub.1-W.sub.1).sub.m-L.sub.2-G.sub.1, [0609] wherein [0610]
L.sub.1 is absent, or is --O--, --C(.dbd.O)--, --NR.sup.i--,
--NR.sup.hC(.dbd.O)--, or --SO.sub.2--; [0611] W.sub.1 is C.sub.1-4
alkylene; [0612] the subscript m is 0, or 1; [0613] L.sub.2 is
absent, or is --O--, --C(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--,
--C(.dbd.O)--C(.dbd.O)--, --C(.dbd.O)--C(.dbd.O)NR.sup.a--, [0614]
--NR.sup.b--, --C(.dbd.O)NR.sup.c--, --NR.sup.dC(.dbd.O)--,
--NR.sup.jC(.dbd.O)O--, --SO.sub.2--, --SO.sub.2NR.sup.e-- or
--NR.sup.fSO.sub.2--; [0615] G.sub.1 is [0616] H, [0617] --CN,
[0618] C.sub.1-4 alkyl (which alkyl is optionally substituted with
one or more independently selected --CN, OH, halo or phenyl),
[0619] C.sub.3-7 cycloalkyl (which cycloalkyl is optionally
substituted with --NH.sub.2), [0620] 5-6 membered
heterocycloalkenyl containing 1 double bond containing one or more
heteroatoms independently selected from O, N, and S, (which
heterocycloalkenyl is optionally substituted with one or more
independently selected R.sup.9 groups), [0621] 4-10 membered mono,
bi or spirocyclic heterocycloalkyl containing one or more
heteroatoms independently selected from O, N, and S, (which
heterocycloalkyl is optionally substituted with one or more
independently selected R.sup.9 groups), or [0622] 5-6 membered
heteroaryl containing one or more heteroatoms independently
selected from O, N, and S, (which heteroaryl is optionally
substituted with one or more independently selected R.sup.10
groups), or [0623] each R.sup.9 is oxo, or R.sup.10; [0624] each
R.sup.10 is: [0625] --OH, [0626] halo, [0627] --CN, [0628]
C.sub.1-4 alkyl (which alkyl is optionally substituted with one or
more independently selected OH, halo, or phenyl), [0629] C.sub.1-4
alkoxy, [0630] C.sub.3-7 cycloalkyl, [0631] phenyl, [0632]
--SO.sub.2CH.sub.3, [0633] --C(.dbd.O)C.sub.1-4 alkoxy, [0634]
--C(.dbd.O)C.sub.1-4 alkyl, or [0635] --NR.sup.gC(.dbd.O)C.sub.1-4
alkyl; and [0636] each R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e,
R.sup.f, R.sup.g, R.sup.h, R.sup.i, and R.sup.j is independently
selected from H, or C.sub.1-4 alkyl; [0637] or a pharmaceutically
acceptable salt, or a solvate, or a pharmaceutically acceptable
salt of a solvate thereof; or a biologically active metabolite
thereof. [0638] 2) A compound or pharmaceutically acceptable salt
thereof, according to clause 1, wherein R.sup.1a is F, Cl,
--CH.sub.3 or --C.sub.2H.sub.5. [0639] 3) A compound or
pharmaceutically acceptable salt thereof, according to clause 1,
wherein R.sup.1a is H. [0640] 4) A compound or pharmaceutically
acceptable salt thereof, according to any one of clauses 1-3,
wherein R.sup.1b is F, Cl, --CH.sub.3, --C.sub.2H.sub.5,
--CF.sub.3, --OCH.sub.3, or --OCF.sub.3. [0641] 5) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-3, wherein R.sup.1b is F. [0642] 6) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-5, wherein X is --S-- or --O--. [0643] 7) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-5, wherein X is --S--. [0644] 8) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-5, wherein W is N. [0645] 9) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-5, wherein W is CR.sup.3. [0646] 10) A compound or
pharmaceutically acceptable salt thereof, according to clause 9,
wherein R.sup.3 is H, CN, F, or Cl. [0647] 11) A compound or
pharmaceutically acceptable salt thereof, according to clause 1,
wherein the compound is according to Formula II:
##STR00013##
[0647] wherein the subscript a, Y, Z, R.sup.4, R.sup.5, R.sup.6,
and R.sup.7 are according to clause 1. [0648] 12) A compound or
pharmaceutically acceptable salt thereof, according to clause 1,
wherein the compound is according to Formula III:
##STR00014##
[0648] wherein the subscript a, Y, Z, R.sup.4, R.sup.5, R.sup.6,
and R.sup.7 are according to clause 1. [0649] 13) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-12, wherein R.sup.4 is --CH.sub.3, or --C.sub.2H.sub.5.
[0650] 14) A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 1-12, wherein R.sup.4 is
--CH.sub.3. [0651] 15) A compound or pharmaceutically acceptable
salt thereof, according to any one of clauses 1-14, wherein R.sup.5
is C.sub.1-4 alkyl. [0652] 16) A compound or pharmaceutically
acceptable salt thereof, according to any one of clauses 1-14,
wherein R.sup.5 is --CH.sub.3, or --C.sub.2H.sub.5. [0653] 17) A
compound or pharmaceutically acceptable salt thereof, according to
any one of clauses 1-14, wherein R.sup.5 is C.sub.1-4 alkyl
substituted with one CN, OH, halo, or --C(.dbd.O)NH.sub.2. [0654]
18) A compound or pharmaceutically acceptable salt thereof,
according to clause 17, wherein R.sup.5 is --CH.sub.3,
--C.sub.2H.sub.5 or --C.sub.3H.sub.7 substituted with one CN, OH,
halo, or --C(.dbd.O)NH.sub.2. [0655] 19) A compound or
pharmaceutically acceptable salt thereof, according to clause 17,
wherein R.sup.5 is --CH.sub.2--CH.sub.2--CN,
--CH.sub.2--CH.sub.2--OH, --CH.sub.2--CF.sub.3, or
--CH.sub.2--CH.sub.2--C(.dbd.O)NH.sub.2. [0656] 20) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-19, wherein Cy is C.sub.3-10 cycloalkyl. [0657] 21) A
compound or pharmaceutically acceptable salt thereof, according to
clause 20, wherein Cy is cyclobutyl, cyclopentyl or cyclohexyl.
[0658] 22) A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 1-19, wherein Cy is 4-10 membered
mono or bicyclic heterocycloalkyl containing one or more
heteroatoms independently selected from O, N, and S. [0659] 23) A
compound or pharmaceutically acceptable salt thereof, according to
clause 22, wherein Cy is oxetanyl, azetidinyl, tetrahydropyranyl,
pyrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, or thiomorpholinyl. [0660] 24) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-19, wherein Cy is 4-7 membered heterocycloalkenyl
containing 1 double bond, containing one or more heteroatoms
independently selected from O, N, and S. [0661] 25) A compound or
pharmaceutically acceptable salt thereof, according to clause 24,
wherein Cy is dihydrofuranyl, dihydrothiazolyl, dihydrooxazolyl,
dihydropyranyl, or dihydrothiopyranyl. [0662] 26) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-25, wherein the subscript a is 1 or 2, and R.sup.7 is OH,
oxo, F, Cl, or --CH.sub.3. [0663] 27) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-25, wherein the subscript a is 0. [0664] 28) A compound
or pharmaceutically acceptable salt thereof, according to any one
of clauses 1-27, wherein R.sup.8 is
-(L.sub.1-W.sub.1).sub.m-L.sub.2-G.sub.1. [0665] 29) A compound
according to Formula I, II, or III, wherein the compound is
according to Formula IVa, IVb, IVc or IVd:
##STR00015##
[0665] wherein Y, Z, R.sup.6, L.sub.1, W.sub.1, L.sub.2, G.sub.1
and the subscript m are according to clause 1. [0666] 30) A
compound or pharmaceutically acceptable salt thereof, according to
clause 28, or 29, wherein the subscript m is 1, L.sub.1 is absent.
[0667] 31) A compound or pharmaceutically acceptable salt thereof,
according to clause 28, or 29, wherein the subscript m is 1,
L.sub.1 is --C(.dbd.O)--, or --SO.sub.2--. [0668] 32) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 28-31, wherein the subscript m is 1, and W.sub.1 is
C.sub.1-4 alkylene. [0669] 33) A compound or pharmaceutically
acceptable salt thereof, according to clause 32, wherein the
subscript m is 1, L.sub.1 is as defined above and W.sub.1 is
--CH.sub.2--, --CH.sub.2--CH.sub.2--, --C(CH.sub.3)H--,
--CH.sub.2--CH.sub.2--CH.sub.2--, or --CH.sub.2--C(CH.sub.3)H--.
[0670] 34) A compound or pharmaceutically acceptable salt thereof,
according to clause 28, or 29, wherein the subscript m is 0. [0671]
35) A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 28-34, wherein L.sub.2 is absent.
[0672] 36) A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 28-34, wherein L.sub.2 is --O--.
[0673] 37) A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 28-34, wherein L.sub.2 is
--C(.dbd.O)--. [0674] 38) A compound or pharmaceutically acceptable
salt thereof, according to any one of clauses 28-34, wherein
L.sub.2 is --C(.dbd.O)O-- or --OC(.dbd.O)--. [0675] 39) A compound
or pharmaceutically acceptable salt thereof, according to any one
of clauses 28-34, wherein L.sub.2 is
--C(.dbd.O)--C(.dbd.O)NR.sup.a--. [0676] 40) A compound or
pharmaceutically acceptable salt thereof, according to clause 39,
wherein R.sup.a is H. [0677] 41) A compound or pharmaceutically
acceptable salt thereof, according to any one of clauses 28-34,
wherein L.sub.2 is --NR.sup.b--. [0678] 42) A compound or
pharmaceutically acceptable salt thereof, according to clause 41,
wherein R.sup.b is H. [0679] 43) A compound or pharmaceutically
acceptable salt thereof, according to any one of clauses 28-34,
wherein L.sub.2 is --C(.dbd.O)NR.sup.c--. [0680] 44) A compound or
pharmaceutically acceptable salt thereof, according to clause 41,
wherein R.sup.c is H, --CH.sub.3, or --CH.sub.2--CH.sub.3. [0681]
45) A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 28-34, wherein L.sub.2 is
--NR.sup.dC(.dbd.O)--. [0682] 46) A compound or pharmaceutically
acceptable salt thereof, according to clause 45, wherein R.sup.d is
H, --CH.sub.3, or --CH.sub.2--CH.sub.3. [0683] 47) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 28-34, wherein L.sub.2 is --SO.sub.2--. [0684] 48) A
compound or pharmaceutically acceptable salt thereof, according to
any one of clauses 28-34, wherein L.sub.2 is --SO.sub.2NR.sup.e--.
[0685] 49) A compound or pharmaceutically acceptable salt thereof,
according to clause 48, wherein R.sup.e is H, --CH.sub.3, or
--CH.sub.2--CH.sub.3. [0686] 50) A compound or pharmaceutically
acceptable salt thereof, according to any one of clauses 28-34,
wherein L.sub.2 is --NR.sup.fSO.sub.2--. [0687] 51) A compound or
pharmaceutically acceptable salt thereof, according to clause 50,
wherein R.sup.f is H, --CH.sub.3, or --CH.sub.2--CH.sub.3. [0688]
52) A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 28-51, wherein G.sub.1 is H, or CN.
[0689] 53) A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 28-51, wherein G.sub.1 is C.sub.1-4
alkyl. [0690] 54) A compound or pharmaceutically acceptable salt
thereof, according to clause 53, wherein G.sub.1 is --CH.sub.3, or
--CH.sub.2--CH.sub.3. [0691] 55) A compound or pharmaceutically
acceptable salt thereof, according to any one of clauses 28-51,
wherein G.sub.1 is C.sub.1-4 alkyl substituted with --CN, OH, halo
or phenyl. [0692] 56) A compound or pharmaceutically acceptable
salt thereof, according to clause 55, wherein G.sub.1 is
--CF.sub.3, --CH.sub.2--Cl, --CH.sub.2--CN, --CH.sub.2--OH or
--CH.sub.2-Ph. [0693] 57) A compound or pharmaceutically acceptable
salt thereof, according to any one of clauses 28-51, wherein
G.sub.1 is C.sub.3-7 cycloalkyl. [0694] 58) A compound or
pharmaceutically acceptable salt thereof, according to clause 57,
wherein G.sub.1 is cyclopropyl, cyclobutyl, cyclopropyl, or
cyclohexyl. [0695] 59) A compound or pharmaceutically acceptable
salt thereof, according to any one of clauses 28-51, wherein
G.sub.1 is C.sub.3-7 cycloalkyl substituted with --NH.sub.2. [0696]
60) A compound or pharmaceutically acceptable salt thereof,
according to clause 59, wherein G.sub.1 is cyclopropyl, cyclobutyl,
cyclopropyl, or cyclohexyl, each of which is substituted with
--NH.sub.2. [0697] 61) A compound or pharmaceutically acceptable
salt thereof, according to any one of clauses 28-51, wherein
G.sub.1 is 5-6 membered heterocycloalkenyl containing 1 double bond
containing one to three heteroatoms independently selected from O,
N, and S. [0698] 62) A compound or pharmaceutically acceptable salt
thereof, according to clause 61, wherein G.sub.1 is dihydrofuranyl,
dihydrothiazolyl, dihydrooxazolyl, dihydropyranyl, or
dihydrothiopyranyl. [0699] 63) A compound or pharmaceutically
acceptable salt thereof, according to any one of clauses 28-51,
wherein G.sub.1 is 4-10 membered mono, bi or spirocyclic
heterocycloalkyl containing one to three heteroatoms independently
selected from O, N, and S. [0700] 64) A compound or
pharmaceutically acceptable salt thereof, according to clause 63,
wherein G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, thiomorpholinyl, or 2,6-diaza-spiro[3.3]heptane.
[0701] 65) A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 28-51, wherein G.sub.1 is 4-10
membered mono, bi or spirocyclic heterocycloalkyl containing one to
three heteroatoms independently selected from O, N, and S,
substituted with one or two independently selected R.sup.9. [0702]
66) A compound or pharmaceutically acceptable salt thereof,
according to clause 65, wherein G.sub.1 is oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, or
2,6-diaza-spiro[3.3]heptane, each of which is substituted with one
or two independently selected R.sup.9. [0703] 67) A compound or
pharmaceutically acceptable salt thereof, according to clause 65 or
66, wherein R.sup.9 is oxo. [0704] 68) A compound or
pharmaceutically acceptable salt thereof, according to clause 65 or
66, wherein R.sup.9 is R.sup.10 and R.sup.10 is selected from OH,
F, Cl, and --CN. [0705] 69) A compound or pharmaceutically
acceptable salt thereof, according to clause 65 or 66, wherein
R.sup.9 is R.sup.10 and R.sup.10 is selected from --CH.sub.3,
--CH.sub.2--CH.sub.3, --CF.sub.3, --CH.sub.2--CH.sub.2--OH, and
--CH.sub.2-phenyl, [0706] 70) A compound or pharmaceutically
acceptable salt thereof, according to clause 65 or 66, wherein
R.sup.9 is R.sup.10 and R.sup.10 is selected from --OCH.sub.3,
--OCH.sub.2--CH.sub.3, and --OC(CH.sub.3).sub.3. [0707] 71) A
compound or pharmaceutically acceptable salt thereof, according to
clause 65 or 66, wherein R.sup.9 is R.sup.10 and R.sup.10 is
selected from --SO.sub.2CH.sub.3, --C(.dbd.O)OCH.sub.3, and
--C(.dbd.O)CH.sub.3. [0708] 72) A compound or pharmaceutically
acceptable salt thereof, according to clause 65 or 66, wherein each
R.sup.9 is R.sup.10 and R.sup.10 is --NR.sup.gC(.dbd.O)CH.sub.3, or
--NR.sup.gC(.dbd.O)CH.sub.2CH.sub.3. [0709] 73) A compound or
pharmaceutically acceptable salt thereof, according to clause 72,
wherein each R.sup.g is H, --CH.sub.3, or --CH.sub.2CH.sub.3.
[0710] 74) A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 28-51, wherein G.sub.1 is 5-6
membered heteroaryl containing one to three heteroatoms
independently selected from O, N, and S. [0711] 75) A compound or
pharmaceutically acceptable salt thereof, according to clause 74,
wherein G.sub.1 is furanyl, thienyl, pyrolyl, pyrazolyl,
imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl,
thiadiazolyl, pyridyl, pyrazinyl, or pyrimidyl. [0712] 76) A
compound or pharmaceutically acceptable salt thereof, according to
any one of clauses 28-51, wherein G.sub.1 is 5-6 membered
heteroaryl containing one to three heteroatoms independently
selected from O, N, and S, substituted with one or two
independently selected R.sup.10. [0713] 77) A compound or
pharmaceutically acceptable salt thereof, according to clause 76,
wherein G.sub.1 is furanyl, thienyl, pyrolyl, pyrazolyl,
imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl,
thiadiazolyl, pyridyl, pyrazinyl, or pyrimidyl, each of which is
substituted with one or two independently selected R.sup.10. [0714]
78) A compound or pharmaceutically acceptable salt thereof,
according to clause 77, wherein R.sup.10 is selected from OH, F,
Cl, and --CN. [0715] 79) A compound or pharmaceutically acceptable
salt thereof, according to clause 77, wherein R.sup.10 is selected
from --CH.sub.3, --CH.sub.2--CH.sub.3, --CF.sub.3,
--CH.sub.2--CH.sub.2--OH, and --CH.sub.2-phenyl. [0716] 80) A
compound or pharmaceutically acceptable salt thereof, according to
clause 77, wherein R.sup.10 is selected from --OCH.sub.3,
--OCH.sub.2--CH.sub.3, and --OC(CH.sub.3).sub.3. [0717] 81) A
compound or pharmaceutically acceptable salt thereof, according to
clause 77, wherein R.sup.10 is selected from --SO.sub.2CH.sub.3,
--C(.dbd.O)OCH.sub.3, and --C(.dbd.O)CH.sub.3. [0718] 82) A
compound or pharmaceutically acceptable salt thereof, according to
clause 77, wherein each R.sup.10 is --NR.sup.gC(.dbd.O)CH.sub.3, or
--NR.sup.gC(.dbd.O)CH.sub.2CH.sub.3. [0719] 83) A compound or
pharmaceutically acceptable salt thereof, according to clause 82,
wherein each R.sup.g is H, --CH.sub.3, or --CH.sub.2CH.sub.3.
[0720] 84) A compound according to clause 1, wherein the compound
is according to Formula Va, Vb, Vc, or Vd:
##STR00016##
[0720] wherein Y, Z, R.sup.6, W.sub.1, and G.sub.1 are according to
clause 1. [0721] 85) A compound or pharmaceutically acceptable salt
thereof, according to clause 84, wherein W.sub.1 is C.sub.1-4
alkylene. [0722] 86) A compound or pharmaceutically acceptable salt
thereof, according to clause 85, wherein the subscript m is 1,
L.sub.1 is as defined above and W.sub.1 is --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --C(CH.sub.3)H--,
--CH.sub.2--CH.sub.2--CH.sub.2--, or --CH.sub.2--C(CH.sub.3)H--.
[0723] 87) A compound according to clause 1, wherein the compound
is according to Formula VIa, VIb, VIc, or VId:
##STR00017##
[0723] wherein Y, Z, R.sup.6, and G.sub.1 are according to clause
1. [0724] 88) A compound or pharmaceutically acceptable salt
thereof, according to any one of clauses 84-87, wherein G.sub.1 is
4-7 membered heterocycloalkyl containing one or more heteroatoms
independently selected from O, N, and S. [0725] 89) A compound or
pharmaceutically acceptable salt thereof, according to clause 88,
wherein G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, or thiomorpholinyl. [0726] 90) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 84-87, wherein G.sub.1 is 4-7 membered heterocycloalkyl
containing one or more heteroatoms independently selected from O,
N, and S, which heterocycloalkyl is substituted with one or two
independently selected R.sup.9 groups. [0727] 91) A compound or
pharmaceutically acceptable salt thereof, according to clause 90,
wherein G.sub.1 is oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, or thiomorpholinyl, each of which is substituted with
one or two independently selected R.sup.9 groups. [0728] 92) A
compound or pharmaceutically acceptable salt thereof, according to
clause 90 or 91, wherein R.sup.9 is oxo. [0729] 93) A compound or
pharmaceutically acceptable salt thereof, according to clause 90 or
91, wherein R.sup.9 is R.sup.10 and R.sup.10 is selected from OH,
F, Cl, and --CN. [0730] 94) A compound or pharmaceutically
acceptable salt thereof, according to clause 90 or 91, wherein
R.sup.9 is R.sup.10 and R.sup.10 is selected from --CH.sub.3,
--CH.sub.2--CH.sub.3, --CF.sub.3, --CH.sub.2--CH.sub.2--OH, and
--CH.sub.2-phenyl, [0731] 95) A compound or pharmaceutically
acceptable salt thereof, according to clause 90 or 91, wherein
R.sup.9 is R.sup.10 and R.sup.10 is selected from --OCH.sub.3,
--OCH.sub.2--CH.sub.3, and --OC(CH.sub.3).sub.3. [0732] 96) A
compound or pharmaceutically acceptable salt thereof, according to
clause 90 or 91, wherein R.sup.9 is R.sup.10 and R.sup.10 is
selected from --SO.sub.2CH.sub.3, --C(.dbd.O)OCH.sub.3, and
--C(.dbd.O)CH.sub.3. [0733] 97) A compound or pharmaceutically
acceptable salt thereof, according to clause 90 or 91, wherein
R.sup.9 is R.sup.10 and R.sup.10 is --NR.sup.gC(.dbd.O)CH.sub.3, or
--NR.sup.gC(.dbd.O)CH.sub.2CH.sub.3. [0734] 98) A compound or
pharmaceutically acceptable salt thereof, according to clause 90 or
91, wherein each R.sup.g is H, --CH.sub.3, or --CH.sub.2CH.sub.3.
[0735] 99) A compound or pharmaceutically acceptable salt thereof,
according to anyone of clauses 1-98, wherein R.sup.6 is H,
--CH.sub.3 or F. [0736] 100) A compound or pharmaceutically
acceptable salt thereof, according to anyone of clauses 1-98,
wherein R.sup.6 is --CH.sub.3. [0737] 101) A compound or
pharmaceutically acceptable salt thereof, according to anyone of
clauses 1-100, wherein Y is N and Z is CH. [0738] 102) A compound
or pharmaceutically acceptable salt thereof, according to anyone of
clauses 1-100, wherein Y is CH and Z is N. [0739] 103) A compound
or pharmaceutically acceptable salt thereof, according to anyone of
clauses 1-102, wherein the compound is selected from the compounds
of Table II. [0740] 104) A pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a pharmaceutically
effective amount of a compound according to any one of clauses
1-103. [0741] 105) A pharmaceutical composition according to clause
104, comprising a further therapeutic agent. [0742] 106) A compound
or pharmaceutically acceptable salt thereof, according to any one
of clauses 1-103, or a pharmaceutical composition according to
clause 104 or 105, for use in medicine. [0743] 107) A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-103, or a pharmaceutical composition according to clause
104 or 105, for use in the treatment of fibrotic diseases,
proliferative diseases, inflammatory diseases, autoimmune diseases,
respiratory diseases, cardiovascular diseases, neurodegenerative
diseases, dermatological disorders, and/or abnormal angiogenesis
associated diseases. [0744] 108) A compound or pharmaceutically
acceptable salt thereof, according to any one of clauses 1-103, or
a pharmaceutical composition according to clause 104 or 105, for
use in the treatment of inflammatory pulmonary fibrosis. [0745]
109) The use of a compound or pharmaceutically acceptable salt
thereof or the pharmaceutical composition according to clause 107
or 108, wherein said compound or pharmaceutical composition is
administered in combination with a further therapeutic agent.
[0746] 110) A method for the treatment, or prevention of diseases
or conditions selected from fibrotic diseases, proliferative
diseases, inflammatory diseases, autoimmune diseases, respiratory
diseases, cardiovascular diseases, neurodegenerative diseases,
dermatological disorders, and/or abnormal angiogenesis associated
diseases, comprising administering an amount of compound according
to any one of clauses 1 to 103, or the pharmaceutical composition
according any one of clauses 104 or 105, sufficient to effect said
treatment, or prevention. [0747] 111) A method for the treatment,
or prevention of inflammatory pulmonary fibrosis, comprising
administering an amount of compound according to any one of clauses
1 to 103, or the pharmaceutical composition according any one of
clauses 104 or 105, sufficient to effect said treatment, or
prevention. [0748] 112) The method according to clause 110 or 111,
wherein the compound, or the pharmaceutical composition, is
administered in combination with a further therapeutic agent.
[0749] 113) The pharmaceutical composition according to clause 105,
or the use according to clause 109, or the method according to
clause 112, wherein the further therapeutic agent is for the
treatment of fibrotic diseases, proliferative diseases,
inflammatory diseases, autoimmune diseases, respiratory diseases,
cardiovascular diseases, neurodegenerative diseases, dermatological
disorders, and/or abnormal angiogenesis associated diseases. [0750]
114) The pharmaceutical composition according to clause 105, or the
use according to clause 109, or the method according to clause 112,
wherein the further therapeutic agent is for the treatment of
inflammatory pulmonary fibrosis.
Pharmaceutical Compositions
[0751] When employed as a pharmaceutical, a compound of the
invention is typically administered in the form of a pharmaceutical
composition. Such compositions can be prepared in a manner well
known in the pharmaceutical art and comprise at least one active
compound of the invention according to Formula I. Generally, a
compound of the invention is administered in a pharmaceutically
effective amount. The amount of compound of the invention actually
administered will typically be determined by a physician, in the
light of the relevant circumstances, including the condition to be
treated, the chosen route of administration, the actual compound of
the invention administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[0752] The pharmaceutical compositions of this invention can be
administered by a variety of routes including oral, rectal,
transdermal, subcutaneous, intra-articular, intravenous,
intramuscular, and intranasal. Depending on the intended route of
delivery, a compound of the invention is preferably formulated as
either injectable or oral compositions or as salves, as lotions or
as patches all for transdermal administration.
[0753] The compositions for oral administration can take the form
of bulk liquid solutions or suspensions, or bulk powders. More
commonly, however, the compositions are presented in unit dosage
forms to facilitate accurate dosing. The term `unit dosage forms`
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient, vehicle or carrier. Typical unit dosage
forms include prefilled, premeasured ampules or syringes of the
liquid compositions or pills, tablets, capsules or the like in the
case of solid compositions. In such compositions, the compound of
the invention according to Formula I is usually a minor component
(from about 0.1 to about 50% by weight or preferably from about 1
to about 40% by weight) with the remainder being various vehicles
or carriers and processing aids helpful for forming the desired
dosing form.
[0754] Liquid forms suitable for oral administration may include a
suitable aqueous or non-aqueous vehicle with buffers, suspending
and dispensing agents, colorants, flavors and the like. Solid forms
may include, for example, any of the following ingredients, or
compound of the inventions of a similar nature: a binder such as
microcrystalline cellulose, gum tragacanth or gelatin; an excipient
such as starch or lactose, a disintegrating agent such as alginic
acid, Primogel, or corn starch; a lubricant such as magnesium
stearate; a glidant such as colloidal silicon dioxide; a sweetening
agent such as sucrose or saccharin; or a flavoring agent such as
peppermint or orange flavoring.
[0755] Injectable compositions are typically based upon injectable
sterile saline or phosphate-buffered saline or other injectable
carriers known in the art. As before, the active compound of the
invention according to Formula I in such compositions is typically
a minor component, often being from about 0.05 to 10% by weight
with the remainder being the injectable carrier and the like.
[0756] Transdermal compositions are typically formulated as a
topical ointment or cream containing the active ingredient(s),
generally in an amount ranging from about 0.01 to about 20% by
weight, preferably from about 0.1 to about 20% by weight,
preferably from about 0.1 to about 10% by weight, and more
preferably from about 0.5 to about 15% by weight. When formulated
as an ointment, the active ingredients will typically be combined
with either a paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream
with, for example an oil-in-water cream base. Such transdermal
formulations are well-known in the art and generally include
additional ingredients to enhance the dermal penetration of
stability of the active ingredients or the formulation. All such
known transdermal formulations and ingredients are included within
the scope of this invention.
[0757] A compound of the invention can also be administered by a
transdermal device. Accordingly, transdermal administration can be
accomplished using a patch either of the reservoir or porous
membrane type, or of a solid matrix variety.
[0758] The above-described components for orally administrable,
injectable or topically administrable compositions are merely
representative. Other materials as well as processing techniques
and the like are set forth in Part 8 of Remington's Pharmaceutical
Sciences, 17.sup.th edition, 1985, Mack Publishing Company, Easton,
Pa., which is incorporated herein by reference.
[0759] A compound of the invention can also be administered in
sustained release forms or from sustained release drug delivery
systems. A description of representative sustained release
materials can be found in Remington's Pharmaceutical Sciences.
[0760] The following formulation examples illustrate representative
pharmaceutical compositions that may be prepared in accordance with
this invention. The present invention, however, is not limited to
the following pharmaceutical compositions.
Formulation 1--Tablets
[0761] A compound of the invention according to Formula I may be
admixed as a dry powder with a dry gelatin binder in an approximate
1:2 weight ratio. A minor amount of magnesium stearate may be added
as a lubricant. The mixture may be formed into 240-270 mg tablets
(80-90 mg of active compound of the invention according to Formula
I per tablet) in a tablet press.
Formulation 2--Capsules
[0762] A compound of the invention according to Formula I may be
admixed as a dry powder with a starch diluent in an approximate 1:1
weight ratio. The mixture may be filled into 250 mg capsules (125
mg of active compound of the invention according to Formula I per
capsule).
Formulation 3--Liquid
[0763] A compound of the invention according to Formula I (125 mg),
may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the
resultant mixture may be blended, passed through a No. 10 mesh U.S.
sieve, and then mixed with a previously made solution of
microcrystalline cellulose and sodium carboxymethyl cellulose
(11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color
may be diluted with water and added with stirring. Sufficient water
may then be added with stirring. Further sufficient water may be
then added to produce a total volume of 5 mL.
Formulation 4--Tablets
[0764] A compound of the invention according to Formula I may be
admixed as a dry powder with a dry gelatin binder in an approximate
1:2 weight ratio. A minor amount of magnesium stearate may be added
as a lubricant. The mixture may be formed into 450-900 mg tablets
(150-300 mg of active compound of the invention according to
Formula I) in a tablet press.
Formulation 5--Injection
[0765] A compound of the invention according to Formula I may be
dissolved or suspended in a buffered sterile saline injectable
aqueous medium to a concentration of approximately 5 mg/mL.
Formulation 6--Topical
[0766] Stearyl alcohol (250 g) and a white petrolatum (250 g) may
be melted at about 75.degree. C. and then a mixture of A compound
of the invention according to Formula I (50 g) methylparaben (0.25
g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and
propylene glycol (120 g) dissolved in water (about 370 g) may be
added and the resulting mixture may be stirred until it
congeals.
Methods of Treatment
[0767] In one embodiment, the present invention provides compounds
of the invention, or pharmaceutical compositions comprising a
compound of the invention, for use in medicine. In a particular
embodiment, the present invention provides compounds of the
invention or pharmaceutical compositions comprising a compound of
the invention, for use in the prophylaxis and/or treatment of
fibrotic diseases, proliferative diseases, inflammatory diseases,
autoimmune diseases, respiratory diseases, cardiovascular diseases,
neurodegenerative diseases, dermatological disorders, and/or
abnormal angiogenesis associated diseases.
[0768] In another embodiment, the present invention provides
compounds of the invention, or pharmaceutical compositions
comprising a compound of the invention for use in the manufacture
of a medicament for use in the prophylaxis and/or treatment of
fibrotic diseases, proliferative diseases, inflammatory diseases,
autoimmune diseases, respiratory diseases, cardiovascular diseases,
neurodegenerative diseases, dermatological disorders, and/or
abnormal angiogenesis associated diseases.
[0769] In one embodiment, the present invention provides
pharmaceutical compositions comprising a compound of the invention,
and another therapeutic agent. In a particular embodiment, the
other therapeutic agent is a fibrotic diseases, proliferative
diseases, inflammatory diseases, autoimmune diseases, respiratory
diseases, cardiovascular diseases, neurodegenerative diseases,
dermatological disorders, and/or abnormal angiogenesis associated
diseases treatment agent.
[0770] In additional method of treatment aspects, this invention
provides methods of prophylaxis and/or treatment of a mammal
afflicted with fibrotic diseases, proliferative diseases,
inflammatory diseases, autoimmune diseases, respiratory diseases,
cardiovascular diseases, neurodegenerative diseases, dermatological
disorders, and/or abnormal angiogenesis associated diseases, which
methods comprise the administration of an effective amount of a
compound of the invention or one or more of the pharmaceutical
compositions herein described for the treatment or prophylaxis of
said condition.
[0771] In one embodiment, the present invention provides compounds
of the invention or pharmaceutical compositions comprising a
compound of the invention, for use in the prophylaxis and/or
treatment of fibrotic diseases. In a particular embodiment, the
fibrotic disease is selected from idiopathic pulmonary fibrosis
(IPF), cystic fibrosis, other diffuse parenchymal lung diseases of
different etiologies including iatrogenic drug-induced fibrosis,
occupational and/or environmental induced fibrosis, granulomatous
diseases (sarcoidosis, hypersensitivity pneumonia), collagen
vascular disease, alveolar proteinosis, langerhans cell
granulomatosis, lymphangioleiomyomatosis, inherited diseases
(Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis,
metabolic storage disorders, familial interstitial lung disease),
radiation induced fibrosis, chronic obstructive pulmonary disease
(COPD), scleroderma, bleomycin induced pulmonary fibrosis, chronic
asthma, silicosis, asbestos induced pulmonary fibrosis, acute
respiratory distress syndrome (ARDS), kidney fibrosis,
tubulointerstitium fibrosis, glomerular nephritis, focal segmental
glomerular sclerosis, IgA nephropathy, hypertension, Alport, gut
fibrosis, liver fibrosis, cirrhosis, alcohol induced liver
fibrosis, toxic/drug induced liver fibrosis, hemochromatosis,
nonalcoholic steatohepatitis (NASH), biliary duct injury, primary
biliary cirrhosis, infection induced liver fibrosis, viral induced
liver fibrosis, and autoimmune hepatitis, corneal scarring,
hypertrophic scarring, Dupuytren disease, keloids, cutaneous
fibrosis, cutaneous scleroderma, systemic sclerosis, spinal cord
injury/fibrosis, myelofibrosis, vascular restenosis,
atherosclerosis, arteriosclerosis, Wegener's granulomatosis,
Peyronie's disease, or chronic lymphocytic. More particularly, the
fibrotic diseases is idiopathic pulmonary fibrosis (IPF).
[0772] In another embodiment, the present invention provides
compounds of the invention, or pharmaceutical compositions
comprising a compound of the invention for use in the manufacture
of a medicament for use in the prophylaxis and/or treatment of
fibrotic diseases. In a particular embodiment, the fibrotic disease
is selected from idiopathic pulmonary fibrosis (IPF), cystic
fibrosis, other diffuse parenchymal lung diseases of different
etiologies including iatrogenic drug-induced fibrosis, occupational
and/or environmental induced fibrosis, granulomatous diseases
(sarcoidosis, hypersensitivity pneumonia), collagen vascular
disease, alveolar proteinosis, langerhans cell granulomatosis,
lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak
Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage
disorders, familial interstitial lung disease), radiation induced
fibrosis, chronic obstructive pulmonary disease (COPD),
scleroderma, bleomycin induced pulmonary fibrosis, chronic asthma,
silicosis, asbestos induced pulmonary fibrosis, acute respiratory
distress syndrome (ARDS), kidney fibrosis, tubulointerstitium
fibrosis, glomerular nephritis, focal segmental glomerular
sclerosis, IgA nephropathy, hypertension, Alport, gut fibrosis,
liver fibrosis, cirrhosis, alcohol induced liver fibrosis,
toxic/drug induced liver fibrosis, hemochromatosis, nonalcoholic
steatohepatitis (NASH), biliary duct injury, primary biliary
cirrhosis, infection induced liver fibrosis, viral induced liver
fibrosis, and autoimmune hepatitis, corneal scarring, hypertrophic
scarring, Dupuytren disease, keloids, cutaneous fibrosis, cutaneous
scleroderma, systemic sclerosis, spinal cord injury/fibrosis,
myelofibrosis, vascular restenosis, atherosclerosis,
arteriosclerosis, Wegener's granulomatosis, Peyronie's disease, or
chronic lymphocytic. More particularly, the fibrotic disease is
idiopathic pulmonary fibrosis (IPF).
[0773] In additional method of treatment aspects, this invention
provides methods of prophylaxis and/or treatment of a mammal
afflicted with fibrotic diseases, which methods comprise the
administration of an effective amount of a compound of the
invention or one or more of the pharmaceutical compositions herein
described for the treatment or prophylaxis of said condition. In a
particular embodiment, the fibrotic disease is selected from
idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuse
parenchymal lung diseases of different etiologies including
iatrogenic drug-induced fibrosis, occupational and/or environmental
induced fibrosis, granulomatous diseases (sarcoidosis,
hypersensitivity pneumonia), collagen vascular disease, alveolar
proteinosis, langerhans cell granulomatosis,
lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak
Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage
disorders, familial interstitial lung disease), radiation induced
fibrosis, chronic obstructive pulmonary disease (COPD),
scleroderma, bleomycin induced pulmonary fibrosis, chronic asthma,
silicosis, asbestos induced pulmonary fibrosis, acute respiratory
distress syndrome (ARDS), kidney fibrosis, tubulointerstitium
fibrosis, glomerular nephritis, focal segmental glomerular
sclerosis, IgA nephropathy, hypertension, Alport, gut fibrosis,
liver fibrosis, cirrhosis, alcohol induced liver fibrosis,
toxic/drug induced liver fibrosis, hemochromatosis, nonalcoholic
steatohepatitis (NASH), biliary duct injury, primary biliary
cirrhosis, infection induced liver fibrosis, viral induced liver
fibrosis, and autoimmune hepatitis, corneal scarring, hypertrophic
scarring, Dupuytren disease, keloids, cutaneous fibrosis, cutaneous
scleroderma, systemic sclerosis, spinal cord injury/fibrosis,
myelofibrosis, vascular restenosis, atherosclerosis,
arteriosclerosis, Wegener's granulomatosis, Peyronie's disease, or
chronic lymphocytic. More particularly, the fibrotic disease is
idiopathic pulmonary fibrosis (IPF).
[0774] A particular regimen of the present method comprises the
administration to a subject suffering from a fibrotic disease of an
effective amount of a compound of the invention according to
Formula I for a period of time sufficient to reduce the level of
fibrosis in the subject, and preferably terminate the processes
responsible for said fibrosis. A special embodiment of the method
comprises administering of an effective amount of a compound of the
invention according to Formula I to a subject patient suffering
from to the development of idiopathic pulmonary fibrosis, for a
period of time sufficient to reduce or prevent idiopathic pulmonary
fibrosis of said patient, and preferably terminate, the processes
responsible for said idiopathic pulmonary fibrosis.
[0775] In one embodiment, the present invention provides compounds
of the invention or pharmaceutical compositions comprising a
compound of the invention, for use in the prophylaxis and/or
treatment of proliferative diseases. In a particular embodiment,
the proliferative disease is selected from cancer, leukemia,
multiple myeloma and psoriasis.
[0776] In another embodiment, the present invention provides
compounds of the invention, or pharmaceutical compositions
comprising a compound of the invention for use in the manufacture
of a medicament for use in the prophylaxis and/or treatment of
proliferative diseases. In a particular embodiment, the
proliferative disease is selected from cancer, leukemia, multiple
myeloma and psoriasis.
[0777] In additional method of treatment aspects, this invention
provides methods of prophylaxis and/or treatment of a mammal
afflicted with proliferative diseases, which methods comprise the
administration of an effective amount of a compound of the
invention or one or more of the pharmaceutical compositions herein
described for the treatment or prophylaxis of said condition. In a
particular embodiment, the proliferative disease is selected from
cancer, leukemia, multiple myeloma and psoriasis.
[0778] In one embodiment, the present invention provides compounds
of the invention or pharmaceutical compositions comprising a
compound of the invention, for use in the prophylaxis and/or
treatment of inflammatory diseases. In a particular embodiment, the
inflammatory disease is selected from rheumatoid arthritis,
osteoarthritis, allergic airway disease (e.g. asthma), chronic
obstructive pulmonary disease (COPD) and inflammatory bowel
diseases (e.g. Crohn's disease and ulcerative colitis). More
particularly, the inflammatory disease is selected from rheumatoid
arthritis, and chronic obstructive pulmonary disease (COPD).
[0779] In another embodiment, the present invention provides
compounds of the invention, or pharmaceutical compositions
comprising a compound of the invention for use in the manufacture
of a medicament for use in the prophylaxis and/or treatment of
inflammatory diseases. In a particular embodiment, the inflammatory
disease is selected from rheumatoid arthritis, osteoarthritis,
allergic airway disease (e.g. asthma), chronic obstructive
pulmonary disease (COPD) and inflammatory bowel diseases (e.g.
Crohn's disease and ulcerative colitis). More particularly, the
inflammatory disease is selected from rheumatoid arthritis, and
chronic obstructive pulmonary disease (COPD).
[0780] In additional method of treatment aspects, this invention
provides methods of prophylaxis and/or treatment of a mammal
afflicted with inflammatory diseases, which methods comprise the
administration of an effective amount of a compound of the
invention or one or more of the pharmaceutical compositions herein
described for the treatment or prophylaxis of said condition. In a
particular embodiment, the inflammatory disease is selected from
rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g.
asthma), chronic obstructive pulmonary disease (COPD) and
inflammatory bowel diseases (e.g. Crohn's disease and ulcerative
colitis). More particularly the inflammatory disease is selected
from rheumatoid arthritis, and chronic obstructive pulmonary
disease (COPD).
[0781] In one embodiment, the present invention provides compounds
of the invention or pharmaceutical compositions comprising a
compound of the invention, for use in the prophylaxis and/or
treatment of autoimmune diseases. In a particular embodiment, the
autoimmune disease is selected from COPD, asthma (e.g intrinsic
asthma, extrinsic asthma, dust asthma, infantily asthma)
particularly chronic or inveterate asthma (for example late asthma
and airway hyperreponsiveness), bronchitis, including bronchial
asthma, systemic lupus erythematosus (SLE), cutaneous lupus
erythrematosis, lupus nephritis, dermatomyositis, Sjogren's
syndrome, multiple sclerosis, psoriasis, dry eye disease, type I
diabetes mellitus and complications associated therewith, atopic
eczema (atopic dermatitis), thyroiditis (Hashimoto's and autoimmune
thyroiditis), contact dermatitis and further eczematous dermatitis,
inflammatory bowel disease (e.g. Crohn's disease and ulcerative
colitis), atherosclerosis and amyotrophic lateral sclerosis.
Particularly, the autoimmune disease is selected from COPD, asthma,
systemic lupus erythematosis, type I diabetes mellitus and
inflammatory bowel disease.
[0782] In another embodiment, the present invention provides
compounds of the invention, or pharmaceutical compositions
comprising a compound of the invention for use in the manufacture
of a medicament for use in the prophylaxis and/or treatment of
autoimmune diseases. In a particular embodiment, the autoimmune
disease is selected from COPD, asthma (e.g intrinsic asthma,
extrinsic asthma, dust asthma, infantily asthma) particularly
chronic or inveterate asthma (for example late asthma and airway
hyperreponsiveness), bronchitis, including bronchial asthma,
systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis,
lupus nephritis, dermatomyositis, Sjogren's syndrome, multiple
sclerosis, psoriasis, dry eye disease, type I diabetes mellitus and
complications associated therewith, atopic eczema (atopic
dermatitis), thyroiditis (Hashimoto's and autoimmune thyroiditis),
contact dermatitis and further eczematous dermatitis, inflammatory
bowel disease (e.g. Crohn's disease and ulcerative colitis),
atherosclerosis and amyotrophic lateral sclerosis. Particularly,
the autoimmune disease is selected from COPD, asthma, systemic
lupus erythematosis, type I diabetes mellitus and inflammatory
bowel disease.
[0783] In additional method of treatment aspects, this invention
provides methods of prophylaxis and/or treatment of a mammal
afflicted with autoimmune diseases, which methods comprise the
administration of an effective amount of a compound of the
invention or one or more of the pharmaceutical compositions herein
described for the treatment or prophylaxis of said condition. In a
particular embodiment, the autoimmune disease is selected from
COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma,
infantily asthma) particularly chronic or inveterate asthma (for
example late asthma and airway hyperreponsiveness), bronchitis,
including bronchial asthma, systemic lupus erythematosus (SLE),
cutaneous lupus erythrematosis, lupus nephritis, dermatomyositis,
Sjogren's syndrome, multiple sclerosis, psoriasis, dry eye disease,
type I diabetes mellitus and complications associated therewith,
atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's and
autoimmune thyroiditis), contact dermatitis and further eczematous
dermatitis, inflammatory bowel disease (e.g. Crohn's disease and
ulcerative colitis), atherosclerosis and amyotrophic lateral
sclerosis. Particularly, the autoimmune disease is selected from
COPD, asthma, systemic lupus erythematosis, type I diabetes
mellitus and inflammatory bowel disease.
[0784] In one embodiment, the present invention provides compounds
of the invention or pharmaceutical compositions comprising a
compound of the invention, for use in the prophylaxis and/or
treatment of respiratory diseases. In a particular embodiment, the
respiratory disease is selected from asthma, adult respiratory
distress syndrome and allergic (extrinsic) asthma, non-allergic
(intrinsic) asthma, acute severe asthma, chronic asthma, clinical
asthma, nocturnal asthma, allergen-induced asthma,
aspirin-sensitive asthma, exercise-induced asthma, isocapnic
hyperventilation, child onset asthma, adult-onset asthma,
cough-variant asthma, occupational asthma, steroid-resistant
asthma, seasonal asthma, seasonal allergic rhinitis, perennial
allergic rhinitis, chronic obstructive pulmonary disease, including
chronic bronchitis or emphysema, pulmonary hypertension,
interstitial lung fibrosis and/or airway inflammation and cystic
fibrosis, and hypoxia.
[0785] In another embodiment, the present invention provides
compounds of the invention, or pharmaceutical compositions
comprising a compound of the invention for use in the manufacture
of a medicament for use in the prophylaxis and/or treatment of
respiratory diseases. In a particular embodiment, the respiratory
disease is selected from asthma, adult respiratory distress
syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic)
asthma, acute severe asthma, chronic asthma, clinical asthma,
nocturnal asthma, allergen-induced asthma, aspirin-sensitive
asthma, exercise-induced asthma, isocapnic hyperventilation, child
onset asthma, adult-onset asthma, cough-variant asthma,
occupational asthma, steroid-resistant asthma, seasonal asthma,
seasonal allergic rhinitis, perennial allergic rhinitis, chronic
obstructive pulmonary disease, including chronic bronchitis or
emphysema, pulmonary hypertension, interstitial lung fibrosis
and/or airway inflammation and cystic fibrosis, and hypoxia.
[0786] In additional method of treatment aspects, this invention
provides methods of prophylaxis and/or treatment of a mammal
afflicted with respiratory diseases, which methods comprise the
administration of an effective amount of a compound of the
invention or one or more of the pharmaceutical compositions herein
described for the treatment or prophylaxis of said condition. In a
particular embodiment, the respiratory disease is selected from
asthma, adult respiratory distress syndrome and allergic
(extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe
asthma, chronic asthma, clinical asthma, nocturnal asthma,
allergen-induced asthma, aspirin-sensitive asthma, exercise-induced
asthma, isocapnic hyperventilation, child onset asthma, adult-onset
asthma, cough-variant asthma, occupational asthma,
steroid-resistant asthma, seasonal asthma, seasonal allergic
rhinitis, perennial allergic rhinitis, chronic obstructive
pulmonary disease, including chronic bronchitis or emphysema,
pulmonary hypertension, interstitial lung fibrosis and/or airway
inflammation and cystic fibrosis, and hypoxia.
[0787] In one embodiment, the present invention provides compounds
of the invention or pharmaceutical compositions comprising a
compound of the invention, for use in the prophylaxis and/or
treatment of cardiovascular diseases. In a particular embodiment,
the cardiovascular disease is selected from arrhythmia (atrial or
ventricular or both), atherosclerosis and its sequelae, angina,
cardiac rhythm disturbances, myocardial ischemia, myocardial
infarction, cardiac or vascular aneurysm, vasculitis, stroke,
peripheral obstructive arteriopathy of a limb, an organ, or a
tissue, reperfusion injury following ischemia of the brain, heart,
kidney or other organ or tissue, endotoxic, surgical, or traumatic
shock, hypertension, valvular heart disease, heart failure,
abnormal blood pressure, shock, vasoconstriction (including that
associated with migraines), vascular abnormality, inflammation,
insufficiency limited to a single organ or tissue.
[0788] In another embodiment, the present invention provides
compounds of the invention, or pharmaceutical compositions
comprising a compound of the invention for use in the manufacture
of a medicament for use in the prophylaxis and/or treatment of
cardiovascular diseases. In a particular embodiment, the
cardiovascular disease is selected from arrhythmia (atrial or
ventricular or both), atherosclerosis and its sequelae, angina,
cardiac rhythm disturbances, myocardial ischemia, myocardial
infarction, cardiac or vascular aneurysm, vasculitis, stroke,
peripheral obstructive arteriopathy of a limb, an organ, or a
tissue, reperfusion injury following ischemia of the brain, heart,
kidney or other organ or tissue, endotoxic, surgical, or traumatic
shock, hypertension, valvular heart disease, heart failure,
abnormal blood pressure, shock, vasoconstriction (including that
associated with migraines), vascular abnormality, inflammation,
insufficiency limited to a single organ or tissue.
[0789] In additional method of treatment aspects, this invention
provides methods of prophylaxis and/or treatment of a mammal
afflicted with cardiovascular diseases, which methods comprise the
administration of an effective amount of a compound of the
invention or one or more of the pharmaceutical compositions herein
described for the treatment or prophylaxis of said condition. In a
particular embodiment, the cardiovascular disease is selected from
arrhythmia (atrial or ventricular or both), atherosclerosis and its
sequelae, angina, cardiac rhythm disturbances, myocardial ischemia,
myocardial infarction, cardiac or vascular aneurysm, vasculitis,
stroke, peripheral obstructive arteriopathy of a limb, an organ, or
a tissue, reperfusion injury following ischemia of the brain,
heart, kidney or other organ or tissue, endotoxic, surgical, or
traumatic shock, hypertension, valvular heart disease, heart
failure, abnormal blood pressure, shock, vasoconstriction
(including that associated with migraines), vascular abnormality,
inflammation, insufficiency limited to a single organ or
tissue.
[0790] In one embodiment, the present invention provides compounds
of the invention or pharmaceutical compositions comprising a
compound of the invention, for use in the prophylaxis and/or
treatment of neurodegenerative diseases. In a particular
embodiment, the neurodegenerative disease is selected from
Alzheimer's disease and other dementias, brain cancer, degenerative
nerve diseases, encephalitis, epilepsy, genetic brain disorders,
head and brain malformations, hydrocephalus, stroke, Parkinson's
disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS or
Lou Gehrig's Disease), Huntington's disease, and prion
diseases.
[0791] In another embodiment, the present invention provides
compounds of the invention, or pharmaceutical compositions
comprising a compound of the invention for use in the manufacture
of a medicament for use in the prophylaxis and/or treatment of
neurodegenerative diseases. In a particular embodiment, the
neurodegenerative disease is selected from Alzheimer's disease and
other dementias, brain cancer, degenerative nerve diseases,
encephalitis, epilepsy, genetic brain disorders, head and brain
malformations, hydrocephalus, stroke, Parkinson's disease, multiple
sclerosis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's
Disease), Huntington's disease, and prion diseases.
[0792] In additional method of treatment aspects, this invention
provides methods of prophylaxis and/or treatment of a mammal
afflicted with neurodegenerative diseases, which methods comprise
the administration of an effective amount of a compound of the
invention or one or more of the pharmaceutical compositions herein
described for the treatment or prophylaxis of said condition. In a
particular embodiment, the neurodegenerative disease is selected
from Alzheimer's disease and other dementias, brain cancer,
degenerative nerve diseases, encephalitis, epilepsy, genetic brain
disorders, head and brain malformations, hydrocephalus, stroke,
Parkinson's disease, multiple sclerosis, amyotrophic lateral
sclerosis (ALS or Lou Gehrig's Disease), Huntington's disease, and
prion diseases.
[0793] In one embodiment, the present invention provides compounds
of the invention or pharmaceutical compositions comprising a
compound of the invention, for use in the prophylaxis and/or
treatment of dermatological disorders. In a particular embodiment,
the dermatological disease is selected from atopic dermatitis,
bullous disorders, collagenoses, psoriasis, psoriatic lesions,
dermatitis, contact dermatitis, eczema, pruritus, urticaria,
rosacea, scleroderma, wound healing, scarring, hypertrophic
scarring, keloids, Kawasaki Disease, rosacea, or Sjogren-Larsso
Syndrome.
[0794] In another embodiment, the present invention provides
compounds of the invention, or pharmaceutical compositions
comprising a compound of the invention for use in the manufacture
of a medicament for use in the prophylaxis and/or treatment of
dermatological disorders. In a particular embodiment, the
dermatological disease is selected from atopic dermatitis, bullous
disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis,
contact dermatitis, eczema, pruritus, urticaria, rosacea,
scleroderma, wound healing, scarring, hypertrophic scarring,
keloids, Kawasaki Disease, rosacea, or Sjogren-Larsso Syndrome.
[0795] In additional method of treatment aspects, this invention
provides methods of prophylaxis and/or treatment of a mammal
afflicted with dermatological disorders, which methods comprise the
administration of an effective amount of a compound of the
invention or one or more of the pharmaceutical compositions herein
described for the treatment or prophylaxis of said condition. In a
particular embodiment, the dermatological disease is selected from
atopic dermatitis, bullous disorders, collagenoses, psoriasis,
psoriatic lesions, dermatitis, contact dermatitis, eczema,
pruritus, urticaria, rosacea, scleroderma, wound healing, scarring,
hypertrophic scarring, keloids, Kawasaki Disease, rosacea, or
Sjogren-Larsso Syndrome.
[0796] In one embodiment, the present invention provides compounds
of the invention or pharmaceutical compositions comprising a
compound of the invention, for use in the prophylaxis and/or
treatment of abnormal angiogenesis associated diseases. In a
particular embodiment, the abnormal angiogenesis associated disease
is selected from atherosclerosis, hypertension, tumor growth,
inflammation, rheumatoid arthritis, wet-form macular degeneration,
choroidal neovascularization, retinal neovascularization, diabetic
retinopathy, and glioblastoma multiforma.
[0797] In another embodiment, the present invention provides
compounds of the invention, or pharmaceutical compositions
comprising a compound of the invention for use in the manufacture
of a medicament for use in the prophylaxis and/or treatment of
abnormal angiogenesis associated diseases. In a particular
embodiment, the abnormal angiogenesis associated disease is
selected from atherosclerosis, hypertension, tumor growth,
inflammation, rheumatoid arthritis, wet-form macular degeneration,
choroidal neovascularization, retinal neovascularization, diabetic
retinopathy, and glioblastoma multiforma.
[0798] In additional method of treatment aspects, this invention
provides methods of prophylaxis and/or treatment of a mammal
afflicted with abnormal angiogenesis associated diseases, which
methods comprise the administration of an effective amount of a
compound of the invention or one or more of the pharmaceutical
compositions herein described for the treatment or prophylaxis of
said condition. In a particular embodiment, the abnormal
angiogenesis associated disease is selected from atherosclerosis,
hypertension, tumor growth, inflammation, rheumatoid arthritis,
wet-form macular degeneration, choroidal neovascularization,
retinal neovascularization, diabetic retinopathy, and glioblastoma
multiforma.
[0799] Injection dose levels range from about 0.1 mg/kg/h to at
least 10 mg/kg/h, all for from about 1 to about 120 h and
especially 24 to 96 h. A preloading bolus of from about 0.1 mg/kg
to about 10 mg/kg or more may also be administered to achieve
adequate steady state levels. The maximum total dose is not
expected to exceed about 1 g/day for a 40 to 80 kg human
patient.
[0800] For the prophylaxis and/or treatment of long-term
conditions, such as degenerative conditions, the regimen for
treatment usually stretches over many months or years so oral
dosing is preferred for patient convenience and tolerance. With
oral dosing, one to four (1-4) regular doses daily, especially one
to three (1-3) regular doses daily, typically one to two (1-2)
regular doses daily, and most typically one (1) regular dose daily
are representative regimens. Alternatively for long lasting effect
drugs, with oral dosing, once every other week, once weekly, and
once a day are representative regimens. In particular, dosage
regimen can be every 1-14 days, more particularly 1-10 days, even
more particularly 1-7 days, and most particularly 1-3 days.
[0801] Using these dosing patterns, each dose provides from about 1
to about 1000 mg of a compound of the invention, with particular
doses each providing from about 10 to about 500 mg and especially
about 30 to about 250 mg.
[0802] Transdermal doses are generally selected to provide similar
or lower blood levels than are achieved using injection doses.
[0803] When used to prevent the onset of a condition, a compound of
the invention will be administered to a patient at risk for
developing the condition, typically on the advice and under the
supervision of a physician, at the dosage levels described above.
Patients at risk for developing a particular condition generally
include those that have a family history of the condition, or those
who have been identified by genetic testing or screening to be
particularly susceptible to developing the condition.
[0804] A compound of the invention can be administered as the sole
active agent or it can be administered in combination with other
therapeutic agents, including other compound of the inventions that
demonstrate the same or a similar therapeutic activity and that are
determined to be safe and efficacious for such combined
administration. In a specific embodiment, co-administration of two
(or more) agents allows for significantly lower doses of each to be
used, thereby reducing the side effects seen.
[0805] In one embodiment, a compound of the invention or a
pharmaceutical composition comprising a compound of the invention
is administered as a medicament. In a specific embodiment, said
pharmaceutical composition additionally comprises a further active
ingredient.
[0806] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prophylaxis of a disease involving inflammation, particular
agents include, but are not limited to, immunoregulatory agents
e.g. azathioprine, corticosteroids (e.g. prednisolone or
dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus,
mycophenolate, mofetil, muromonab-CD3 (OKT3, e.g.
Orthocolone.RTM.), ATG, aspirin, acetaminophen, ibuprofen,
naproxen, and piroxicam.
[0807] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prophylaxis of arthritis (e.g. rheumatoid arthritis),
particular agents include but are not limited to analgesics,
non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic
DMARDS (for example but without limitation methotrexate,
leflunomide, sulfasalazine, auranofin, sodium aurothiomalate,
penicillamine, chloroquine, hydroxychloroquine, azathioprine,
tofacitinib, baricitinib, fostamatinib, and cyclosporin), and
biological DMARDS (for example but without limitation infliximab,
etanercept, adalimumab, rituximab, and abatacept).
[0808] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prophylaxis of proliferative disorders, particular agents
include but are not limited to: methotrexate, leukovorin,
adriamycin, prednisone, bleomycin, cyclophosphamide,
5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine,
vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate,
anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g.
Herceptin.TM.), capecitabine, raloxifene hydrochloride, EGFR
inhibitors (e.g. lressa.RTM., Tarceva.TM., Erbitux.TM.), VEGF
inhibitors (e.g. Avastin.TM.), proteasome inhibitors (e.g.
Velcade.TM.) Glivec.RTM. and hsp90 inhibitors (e.g. 17-AAG).
Additionally, the compound of the invention according to Formula I
may be administered in combination with other therapies including,
but not limited to, radiotherapy or surgery. In a specific
embodiment the proliferative disorder is selected from cancer,
myeloproliferative disease or leukaemia.
[0809] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prophylaxis of autoimmune diseases, particular agents
include but are not limited to: glucocorticoids, cytostatic agents
(e.g. purine analogs), alkylating agents, (e.g nitrogen mustards
(cyclophosphamide), nitrosoureas, platinum compound of the
inventions, and others), antimetabolites (e.g. methotrexate,
azathioprine and mercaptopurine), cytotoxic antibiotics (e.g.
dactinomycin anthracyclines, mitomycin C, bleomycin, and
mithramycin), antibodies (e.g. anti-CD20, anti-CD25 or anti-CD3
(OTK3) monoclonal antibodies, Atgam.RTM. and Thymoglobuline.RTM.),
cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g.
IFN-.beta.), TNF binding proteins (e.g. infliximab, etanercept, or
adalimumab), mycophenolate, fingolimod and myriocin.
[0810] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prophylaxis of transplant rejection, particular agents
include but are not limited to: calcineurin inhibitors (e.g.
cyclosporin or tacrolimus (FK506)), mTOR inhibitors (e.g.
sirolimus, everolimus), anti-proliferatives (e.g. azathioprine,
mycophenolic acid), corticosteroids (e.g. prednisolone,
hydrocortisone), antibodies (e.g. monoclonal anti-IL-2R.alpha.
receptor antibodies, basiliximab, daclizumab), polyclonal
anti-T-cell antibodies (e.g. anti-thymocyte globulin (ATG),
anti-lymphocyte globulin (ALG)).
[0811] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prophylaxis of asthma and/or rhinitis and/or COPD,
particular agents include but are not limited to:
beta2-adrenoceptor agonists (e.g. salbutamol, levalbuterol,
terbutaline and bitolterol), epinephrine (inhaled or tablets),
anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral
or inhaled). Long-acting .beta.2-agonists (e.g. salmeterol,
formoterol, bambuterol, and sustained-release oral albuterol),
combinations of inhaled steroids and long-acting bronchodilators
(e.g. fluticasone/salmeterol, budesonide/formoterol), leukotriene
antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast
and zileuton), inhibitors of mediator release (e.g. cromoglycate
and ketotifen), biological regulators of IgE response (e.g.
omalizumab), antihistamines (e.g. ceterizine, cinnarizine,
fexofenadine) and vasoconstrictors (e.g. oxymethazoline,
xylomethazoline, nafazoline and tramazoline).
[0812] Additionally, a compound of the invention may be
administered in combination with emergency therapies for asthma
and/or COPD, such therapies include oxygen or heliox
administration, nebulized salbutamol or terbutaline (optionally
combined with an anticholinergic (e.g. ipratropium), systemic
steroids (oral or intravenous, e.g. prednisone, prednisolone,
methylprednisolone, dexamethasone, or hydrocortisone), intravenous
salbutamol, non-specific beta-agonists, injected or inhaled (e.g.
epinephrine, isoetharine, isoproterenol, metaproterenol),
anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine,
ipratropium), methylxanthines (theophylline, aminophylline,
bamiphylline), inhalation anesthetics that have a bronchodilatory
effect (e.g. isoflurane, halothane, enflurane), ketamine and
intravenous magnesium sulfate.
[0813] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prophylaxis of inflammatory bowel disease (IBD), particular
agents include but are not limited to: glucocorticoids (e.g.
prednisone, budesonide) synthetic disease modifying,
immunomodulatory agents (e.g. methotrexate, leflunomide,
sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine and
cyclosporin) and biological disease modifying, immunomodulatory
agents (infliximab, adalimumab, rituximab, and abatacept).
[0814] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prophylaxis of SLE, particular agents include but are not
limited to: human monoclonal antibodies (belimumab (Benlysta)),
Disease-modifying antirheumatic drugs (DMARDs) such as
antimalarials (e.g. plaquenil, hydroxychloroquine),
immunosuppressants (e.g. methotrexate and azathioprine),
cyclophosphamide and mycophenolic acid, immunosuppressive drugs and
analgesics, such as nonsteroidal anti-inflammatory drugs, opiates
(e.g. dextropropoxyphene and co-codamol), opioids (e.g.
hydrocodone, oxycodone, MS Contin, or methadone) and the fentanyl
duragesic transdermal patch.
[0815] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prophylaxis of psoriasis, particular agents include but are
not limited to: topical treatments such as bath solutions,
moisturizers, medicated creams and ointments containing coal tar,
dithranol (anthralin), corticosteroids like desoximetasone
(Topicort.TM.), fluocinonide, vitamin D3 analogues (for example,
calcipotriol), argan oil and retinoids (etretinate, acitretin,
tazarotene), systemic treatments such as methotrexate,
cyclosporine, retinoids, tioguanine, hydroxyurea, sulfasalazine,
mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid
esters or biologics such as Amevive.TM., Enbrel.TM., Humira.TM.,
Remicade.TM., Raptiva.TM. and ustekinumab (a IL-12 and IL-23
blocker). Additionally, a compound of the invention may be
administered in combination with other therapies including, but not
limited to phototherapy, or photochemotherapy (e.g. psoralen and
ultraviolet A phototherapy (PUVA)).
[0816] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prophylaxis of allergic reaction, particular agents include
but are not limited to: antihistamines (e.g. cetirizine,
diphenhydramine, fexofenadine, levocetirizine), glucocorticoids
(e.g. prednisone, betamethasone, beclomethasone, dexamethasone),
epinephrine, theophylline or anti-leukotrienes (e.g. montelukast or
zafirlukast), anti-cholinergics and decongestants.
[0817] By co-administration is included any means of delivering two
or more therapeutic agents to the patient as part of the same
treatment regime, as will be apparent to the skilled person. Whilst
the two or more agents may be administered simultaneously in a
single formulation, i.e. as a single pharmaceutical composition,
this is not essential. The agents may be administered in different
formulations and at different times.
Chemical Synthetic Procedures
General
[0818] The compound of the invention can be prepared from readily
available starting materials using the following general methods
and procedures. It will be appreciated that where typical or
preferred process conditions (i.e. reaction temperatures, times,
mole ratios of reactants, solvents, pressures, etc.) are given,
other process conditions can also be used unless otherwise stated.
Optimum reaction conditions may vary with the particular reactants
or solvent used, but such conditions can be determined by one
skilled in the art by routine optimization procedures.
[0819] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group as well as suitable conditions for protection and
deprotection are well known in the art (Wuts and Greene 2012).
[0820] The following methods are presented with details as to the
preparation of a compound of the invention as defined hereinabove
and the comparative examples. A compound of the invention may be
prepared from known or commercially available starting materials
and reagents by one skilled in the art of organic synthesis.
[0821] All reagents are of commercial grade and are used as
received without further purification, unless otherwise stated.
Commercially available anhydrous solvents are used for reactions
conducted under inert atmosphere. Reagent grade solvents are used
in all other cases, unless otherwise specified. Column
chromatography is performed on silica gel 60 (35-70 .mu.m). Thin
layer chromatography is carried out using pre-coated silica gel
F-254 plates (thickness 0.25 mm). .sup.1H NMR spectra are recorded
on a Bruker DPX 400 NMR spectrometer (400 MHz or a Bruker Advance
300 NMR spectrometer (300 MHz). Chemical shifts (.delta.) for
.sup.1H NMR spectra are reported in parts per million (ppm)
relative to tetramethylsilane (.delta. 0.00) or the appropriate
residual solvent peak, i.e. CHCl.sub.3 (.delta. 7.27), as internal
reference. Multiplicities are given as singlet (s), doublet (d),
triplet (t), quartet (q), quintuplet (quin), multiplet (m) and
broad (br). Electrospray MS spectra are obtained on a Waters
platform LC/MS spectrometer or with Waters Acquity UPLC with Waters
Acquity PDA detector and SQD mass spectrometer. Columns used: UPLC
BEH C18 1.7 .mu.m 2.1.times.5 mm VanGuard Pre-column with Acquity
UPLC BEH C18 1.7 .mu.m 2.1.times.30 mm Column or Acquity UPLC BEH
C18 1.7 .mu.m 2.1.times.50 mm Column. All the methods are using
MeCN/H.sub.2O gradients. MeCN and H.sub.2O contain either 0.1%
Formic Acid or NH.sub.3 (10 mM). Preparative LC-MS: column used,
Waters XBridge Prep C18 5 .mu.m ODB 30 mm ID.times.100 mm L
(preparative column) and Waters XBridge BEH C18 5 .mu.m 4.6 mm
ID.times.100 mm L (analytical column). All the methods are using
either MeOH/H.sub.2O or MeCN/H.sub.2O gradients. MeOH, MeCN and
H.sub.2O contain either 0.1% Formic Acid or 0.1% Diethylamine.
Microwave heating is performed with a Biotage Initiator.
Celpure.RTM. P65 is a filter agent, commercial product (CAS number
61790-53-2).
[0822] List of abbreviations used in the experimental section:
TABLE-US-00001 .mu.L microliter APMA 4-aminophenylmercuric acetate
app t Apparent triplet AUC Area Under the Curve BAL
Broncho-alveolar lavage BALF Broncho-alveolar lavage fluid br d
Broad doublet Boc tert-Butyloxy-carbonyl br s Broad singlet BSA
Bovine serum albumine br t Broad triplet Cat. Catalytic amount cDNA
copy deoxyribonucleic acid Cpd Compound d doublet DavePhos
2-Dicyclohexylphosphino-2'- (N,N-dimethylamino)biphenyl DCE
Dichloroethane DCM Dichloromethane DDQ
2,3-Dichloro-5,6-dicyano-1,4- benzoquinone DEAD diethyl
azodicarboxylate Desc'd Described in details DIAD Diisopropyl
azodicarboxylate DIPE Diisopropylether DIPEA
N,N-diisopropylethylamine DMA Dimethylacetamide DMF
N,N-dimethylformamide DMSO Dimethylsulfoxide dppf
1,1'-Bis(diphenylphosphino) ferrocene EDC 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide) EDC.cndot.HCl
N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride eq.
Equivalent Et.sub.2O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol
FBS Fetal bovine serum FITC Fluorescein Isothiocyanate Fmoc
9-Fluorenylmethoxycarbonyl g gram h hour HATU
O-(7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium
hexafluorophosphate HOBt Hydroxybenzotriazole HPLC High pressure
liquid chromatography HRP horseradish peroxydase Int Intermediate
JohnPhos (2-Biphenyl)di-tert- butylphosphine kg kilogram L liter
LC-MS Liquid Chromatography- Mass Spectrometry LPC
lysophosphatidylcholine LPA Lysophosphatidic acid m multiplet
m-CPBA 3-Chloroperbenzoic acid MeCN Acetonitrile MeOH Methanol mg
milligram min minute mL millilitre mmol millimoles MMP Matrix
Metallo Proteinase MS Ms'd Mass measured by LC-MS MW Molecular
weight N.A. Not available NBS N-Bromosuccinimide nBuOH n-Butanol
NMR Nuclear Magnetic Resonance PBF phosphate buffered formalin PBS
Phosphate buffered saline PCR Polymerase chain reaction
Pd(amphos)Cl.sub.2 Bis(di-tert-butyl(4-
dimethylaminophenyl)phosphine) dichloropalladium(II)
Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine)palladium(0) Pd/C
Palladium on Carbon 10% Pd.sub.2(dba).sub.3
Tris(dibenzylideneacetone) dipalladium(0) PdCl.sub.2dppf
[1,1'-Bis(diphenylphosphino)ferrocene] dichloropalladium(II)
Pd(OAc).sub.2 Palladium(II) acetate PEG Polyethylene glycol ppm
part-per-million q quadruplet QrtPCR quantitative real-time PCR QTL
quantitative trait loci r.t. Room temperature RNA Ribonucleic acid
Rt retention time s singlet sept septuplet Sphos
2-Dicyclohexylphosphino-2',6'- dimethoxybiphenyl t triplet TBAF
Tetra-n-butylammonium fluoride t-BuOH Tert-butanol TBDPSCl
Tert-butyldiphenylsilyl chloride TBSCl Tert-butyldimethylsilyl
chloride TEA Triethylamine TFA Trifluoroacetic acid THF
Tetrahydrofuran TOOS (N-ethyl-N-(2-hydroxy-3-
sulfopropyl)-3-methylaniline, sodium salt dihydrate TS Tobacco
smoke XantPhos 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene
SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTION
EXAMPLE 1
General Synthetic Methods
1.1. Synthetic Methods Overview
[0823] ##STR00018## [0824] Where R.sup.z is R.sup.5 or an alkyl,
alkenyl or carbonyl group optionally substituted, and halo is F,
Cl, Br or I.
Step i: Method A
[0825] A1 (2 steps): Route using isonitrile reagent then reaction
with HCOOH
[0826] A2 (2 steps): Route using KCN then reaction with HCOOH
Step ii: Consists in One of the Following Methods
[0827] B1: Alkylation with NaH as base in DMF
[0828] B2: Alkylation with K.sub.2CO.sub.3 as base in acetone
Step iii: Consists in One of the Following Methods
[0829] C1: Deformylation under acidic conditions
[0830] C2: Deformylation under basic conditions
Step iv: Consists in One of the Following Methods
[0831] D1 (2 steps): formation of thiourea then cyclisation to give
thiazole derivative
[0832] D2: heteroaromatic nucleophilic substitution
Step v: Consists in One or Several of the Following Methods
[0833] E1a or E1b: Buchwald coupling
[0834] E2: Suzuki coupling
[0835] E3: Negishi coupling
[0836] E4a or E4b: SNAr
[0837] E5a or E5b: Boc deprotection
[0838] E6: Reduction with H.sub.2 in presence of transition metal
catalyst
[0839] E7: Dess-Martin oxidation
[0840] E8: Alkylation
[0841] E9a, E9b or E9c: Amide bond forming reaction
[0842] E10: Reductive amination
[0843] E11: Sulfonylation
[0844] E12: Nucleophilic substitution
[0845] E13: Saponification
[0846] E14: Introduction of hydroxymethyl group
[0847] E15: Introduction of trifluoroacetyl group
[0848] E16: Halogenation
[0849] E17: Copper mediated cyanation
[0850] E18: Silyl protection
[0851] E19: Silyl deprotection
Step vi: Consists in One or Several of the Methods E
Step vii: Consists in One of the Methods C
[0852] Step viii: Consists in One of the Methods D and One or
Several of the Methods E
[0853] D3 (2 steps): heteroaromatic nucleophilic substitution then
suzuki coupling
1.2. General Methods
1.2.1. General Method A1 and A2: Synthesis of Intermediate
Gen-1
##STR00019##
[0854] 1.2.1.1. General Method A1
##STR00020##
[0855] Step i)
[0856] To a solution of amino-heterocycle derivative (1 eq.) in
nBuOH under argon are added successively the aldehyde R.sup.zCHO
(2.5 eq.), MgCl.sub.2 (0.04 eq.) and 1,1,3,3-tetramethylbutyl
isocyanide (1.15 eq.). The reaction mixture is heated at
130.degree. C. from between 3.5 h to overnight, and then
concentrated in vacuo. The residue is partitioned between heptane
and water, stirred for 15 to 40 min, the biphasic solution is
filtered on Celpure.RTM. P65, and the cake is washed with heptane.
The two layers of the filtrate are separated, the organic layer is
washed successively with water, an aqueous 1M NaOH and brine, then
dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the
expected amine which is used directly in the next step.
Step ii)
[0857] A solution of the above prepared compound (1 eq.) in formic
acid is heated at 80.degree. C. for 1 to 4 h. The reaction mixture
is concentrated in vacuo. The residue is then triturated in
Et.sub.2O. The formed precipitate is filtered, rinsed and dried to
afford Intermediate Gen-1.
1.2.1.2. Illustrative Synthesis of Intermediate Gen-1-b:
N-(6-Bromo-2-ethyl-imidazo[1,2-a]pyrazin-3-yl)-formamide
##STR00021##
[0858] Step i)
[0859] To a solution of 5-Bromo-pyrazin-2-ylamine (10 g, 57.47
mmol, 1 eq.) in nBuOH (58 mL) under argon are added successively
propanal (10.37 mL, 143.6 mmol, 2.5 eq.), MgCl.sub.2 (219 mg, 2.29
mmol, 0.04 eq.) and 1,1,3,3-tetramethylbutyl isocyanide (11.6 mL,
66.1 mmol, 1.15 eq.). The reaction mixture is heated at 130.degree.
C. overnight, and then concentrated in vacuo. The residue is
partitioned between heptane (100 mL) and water (100 mL), stirred
for 20 min and the biphasic suspension is filtered on Celpure.RTM.
P65, the cake is washed with heptane (100 mL). The two layers of
the biphasic filtrate are separated, the organic layer is
successively washed with water, an aqueous 1M NaOH solution, then
brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to
afford the expected amine. (NB: A solid remaining on the celite pad
is collected, then re-dissolved with DCM, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford
first batch of the expected amine). The two batches are combined
and used directly in the next step.
[0860] LC-MS: MW (calcd): 352 (.sup.79Br), 354 (.sup.81Br); m/z MW
(obsd): 353 (.sup.79Br M+H), 355 (.sup.81Br M+H)
Step ii)
[0861] A solution of the above prepared compound (11.64 g, 32.9
mmol, 1 eq.) in formic acid (93.12 mL) is heated at 80.degree. C.
for 4 h. The reaction mixture is concentrated in vacuo. The residue
is then triturated in Et.sub.2O; the resulting precipitate is
filtered, rinsed and dried to afford Intermediate Gen-1-b.
[0862] LC-MS: MW (calcd): 268 (.sup.79Br), 270 (.sup.81Br); m/z MW
(obsd): 269 (.sup.79Br M+H), 271 (.sup.81Br M+H)
1.2.1.3. General Method A2
##STR00022##
[0863] Step i)
[0864] To a suspension of amino-heterocycle derivative (1 eq.) in
toluene are added the aldehyde R.sup.zCHO (1 eq.) and benzotriazole
(1.1 eq.). The mixture is stirred at r.t. overnight, then
additional aldehyde reagent (0.5 eq.) is added. After 2 h to 4 h
stirring at r.t., potassium cyanide (1.0 to 1.2 eq.) is added,
followed by EtOH. The reaction mixture is stirred at r.t. for 1 to
5 days (another addition of aldehyde reagent and of potassium
cyanide might be required). The crude product mixture is then
quenched with a 1 M or 3 M NaOH solution. Solvents are evaporated
carefully in vacuo. The residue is diluted with water and EtOAc.
The aqueous layer is extracted with EtOAc, and the combined organic
layers are washed with water, brine, dried over Na.sub.2SO.sub.4
and concentrated in vacuo. A solution of acetyl chloride (2 to 2.1
eq.) in EtOH at 0.degree. C. is added dropwise carefully to a
solution of the crude product mixture in EtOH at 0.degree. C. The
resulting reaction mixture is stirred at r.t. overnight and then
concentrated to dryness to afford the expected amine as
hydrochloride salt.
Step ii)
[0865] A solution of the above prepared amine hydrochloride salt (1
eq.) in formic acid is heated at 90.degree. C. for 2 h. Solvents
are evaporated in vacuo. The residue is dissolved in water. The
mixture is carefully basified with a saturated NaHCO.sub.3 solution
until pH 8-9 is reached. The formed solid is filtered, washed with
water and DIPE and dried to afford Intermediate Gen-1.
Alternatively EtOAc is added to the basic aqueous layer and the
layers are separated. The aqueous layer is further extracted with
EtOAc. The combined organic layers are then washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The residue is triturated with DIPE at r.t. for 1 h, the resulting
solid is separated by filtration and dried to afford Intermediate
Gen-1.
1.2.1.4. Illustrative Synthesis of Intermediate Gen-1-a:
N-(6-Bromo-2-ethyl-imidazo[1,2-b]pyridazin-3-yl)-formamide
##STR00023##
[0866] Step i)
[0867] To a suspension of 6-bromopyridazin-3-amine (26.28 g, 151
mmol, 1 eq.) in toluene (450 mL) are added propanal (11.12 mL, 151
mmol, 1 eq.) and benzotriazole (19.79 g, 166 mmol, 1.1 eq.). The
mixture is stirred at r.t. overnight. Additional propanal (5.56 mL,
75.5 mmol 0.5 eq.) is added. After 2 h stirring at r.t., potassium
cyanide (9.83 g, 151 mmol, 1 eq.) is added, followed by EtOH (1200
mL). The reaction mixture is stirred at r.t. overnight. Propanal
(11.12 mL, 151 mmol, 1 eq.) and potassium cyanide (4.91 g, 75.5
mmol, 0.5 eq.) are added and the reaction is stirred at r.t. for 2
days. The crude product mixture is then quenched with an aqueous 1
M NaOH solution (1000 mL). Solvents are evaporated carefully in
vacuo. The residue is diluted with water and EtOAc. The aqueous
layer is extracted with EtOAc. The combined organic layers are
washed with water and brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. A solution of acetyl chloride (21.2 mL,
300.5 mmol, 2 eq.) in EtOH (600 mL) at 0.degree. C. is added
carefully dropwise to a solution of the crude product mixture in
EtOH (750 mL) at 0.degree. C. The resulting reaction mixture is
stirred at r.t. overnight and then concentrated to dryness to
afford the corresponding
6-Bromo-2-ethyl-imidazo[1,2-b]pyridazin-3-ylamine as hydrochloride
salt.
[0868] LC-MS MW (calcd): 240 (.sup.79Br), 242(.sup.81Br); m/z MW
(obsd): 241 (.sup.79Br M+H), 243 (.sup.81Br M+H)
Step ii)
[0869] A solution of the above prepared
imidazo[1,2-b]pyridazin-3-ylamine hydrochloride salt (27.0 g, 97.0
mmol, 1 eq.) in formic acid (150 mL) is heated at 90.degree. C. for
2 h. Solvents are evaporated in vacuo. The residue is dissolved in
water. The mixture is carefully basified with a saturated
NaHCO.sub.3 solution until pH 8-9 is reached. EtOAc is added and
the layers are separated. The aqueous layer is extracted with EtOAc
five times. The combined organic layers are then washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The residue is triturated with DIPE at r.t. for 1 h, the resulting
solid is separated by filtration and dried to afford Intermediate
Gen-1-a.
[0870] LC-MS MW (calcd): 268 (.sup.79Br), 270 (.sup.81Br); m/z MW
(obsd): 269 (.sup.79Br M+H), 271 (.sup.81Br M+H)
1.2.2. General Methods B1 and B2: Synthesis of Intermediate
Gen-2
##STR00024##
[0871] 1.2.2.1. General Method B1
##STR00025##
[0873] NaH (60% in oil suspension, 1.05 eq.) is slurried in dry DMF
and cooled to -5.degree. C. A suspension of
imidazo[1,2-b]pyridazin-3-ylamine or
imidazo[1,2-a]pyrazin-3-ylamine derivative (1 eq.) in dry DMF is
added, and is stirred for 40 min at -5.degree. C. to allow anion
formation. Then alkyl iodide (1.5 eq.) is added to the reaction
mixture which is stirred at -5.degree. C. and then at 0.degree. C.
or 40.degree. C. until completion. The reaction mixture is quenched
with an aqueous 1 M HCl solution, and diluted with DCM, the layers
are separated, the aqueous layer is extracted twice with DCM. The
combined organic layers are dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The expected product is obtained by
chromatography on silica gel or crystallization.
1.2.2.2. Illustrative Synthesis of Intermediate Gen-2-c:
N-[6-Bromo-2-((E)-styryl)-imidazo[1,2-b]pyridazin-3-yl]-N-methyl-formamid-
e
##STR00026##
[0875] NaH (60% in oil suspension, 4.37 g, 109 mmol, 1.05 eq.) is
slurried in dry DMF (100 mL) and cooled to -5.degree. C. A
suspension of Gen-1-c (35.7 g, 104 mmol, 1 eq.) in dry DMF (200 mL)
is added, and is stirred for 40 min at -5.degree. C. to allow anion
formation. Then methyl iodide (9.71 mL, 156 mmol, 1.5 eq.) is added
to the reaction mixture which is stirred at -5.degree. C. for 30
min and then at 40.degree. C. for 45 min. The reaction mixture is
quenched with an aqueous 1 M HCl solution (1000 mL), and diluted
with DCM (1000 mL), the layers are separated, the aqueous layer is
extracted twice with DCM (300 mL). The combined organic layers are
dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue
is triturated with EtOAc (500 mL) and stirred at r.t. overnight,
the resulting solid is separated by filtration and dried to afford
the expected Intermediate Gen-2-c.
[0876] LC-MS: MW (calcd): 356 (.sup.79Br), 358 (.sup.81Br); m/z MW
(obsd): 357 (.sup.79Br M+H), 359 (.sup.81Br M+H)
1.2.2.3. General Method B2
##STR00027##
[0878] To a suspension of imidazo[1,2-b]pyridazin-3-ylamine or
imidazo[1,2-a]pyrazin-3-ylamine derivative (1 eq.) in acetone are
added potassium carbonate (3 eq.) and alkyl iodide (1.2 eq to 1.9
eq.). The reaction mixture is stirred at a temperature comprised
between r.t. and refluxing temperature until completion. (NB:
additional alkyl iodide may be introduced and stirring continued as
needed to reach completion). The reaction mixture is then filtered
and washed with acetone then DCM, the filtrate is concentrated in
vacuo; alternatively, the reaction mixture is directly concentrated
in vacuo. The residue is partitioned between DCM and water. The
organic layer is separated, and the aqueous layer is further
extracted with DCM. The combined organic layers are then washed
with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. The residue is triturated with Et.sub.2O at r.t. for 1 h,
the resulting solid is separated by filtration and dried to afford
the expected Intermediate.
1.2.2.4. Illustrative Synthesis of Intermediate Gen-2-a:
N-(6-Bromo-2-ethyl-imidazo[1,2-b]pyridazin-3-yl)-N-methyl-formamide
##STR00028##
[0880] To a solution of
N-(6-Bromo-2-ethyl-imidazo[1,2-b]pyridazin-3-yl)-formamide
(Gen-1-a) (7.0 g, 26.0 mmol, 1 eq.) in acetone (300 mL) is added
potassium carbonate (10.79 g, 78.0 mmol, 3 eq.) and methyl iodide
(1.95 mL, 31.2 mmol, 1.2 eq). The reaction mixture is refluxed for
2 h, then more methyl iodide (0.97 mL, 15.75 mmol, 0.5 eq.) is
introduced and stirring is continued for 2 h (this operation is
repeated once more). The reaction mixture is concentrated in vacuo,
the residue is partitioned between DCM and water. The aqueous layer
is further extracted with DCM three times. The combined organic
layers are then washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue is triturated with
Et.sub.2O at r.t. for 1 h, the resulting solid is separated by
filtration and dried to afford Intermediate Gen-2-a.
[0881] LC-MS: MW (calcd): 282 (.sup.79Br), 284 (.sup.81Br); m/z MW
(obsd): 283 (.sup.79Br M+H), 285 (.sup.81Br M+H)
1.2.3. General Methods C1 and C2: Synthesis of Intermediate
Gen-3
##STR00029##
[0882] 1.2.3.1. General Method C1
##STR00030##
[0884] A 4 M HCl solution in dioxane or 1.25 M HCl solution in MeOH
(4 to 12 eq.) is added to a solution of
imidazo[1,2-b]pyridazin-3-yl formamide or
imidazo[1,2-a]pyrazin-3-yl formamide derivative (1 eq.) in MeOH.
The reaction mixture is stirred at a r.t. or refluxed for 3 h. If
the reaction is not complete, additional 4 M HCl solution (1.5 eq.)
is added and stirring is continued until completion. The reaction
mixture is then concentrated in vacuo to afford the expected
intermediate.
1.2.3.2. Illustrative Synthesis of Intermediate Gen-3-a:
(6-Bromo-2-ethyl-imidazo[1,2-b]pyridazin-3-yl)-methyl-amine
##STR00031##
[0886] An aqueous 4 M HCl solution in dioxane (229.0 mL, 915.0
mmol, 12 eq.) is added to a solution of
N-(6-Bromo-2-ethyl-imidazo[1,2-b]pyridazin-3-yl)-N-methyl-formamide
(Gen-2-a) (21.6 g, 76.0 mmol, 1 eq.) in MeOH (600 mL). The reaction
mixture is stirred at r.t. for 3 h. The reaction mixture is then
concentrated in vacuo to afford Intermediate Gen-3-a as
dihydrochloride salt.
[0887] LC-MS: MW (calcd): 254 (.sup.79Br), 256 (.sup.81Br); m/z MW
(obsd): 255 (.sup.79Br M+H), 257 (.sup.81Br M+H)
1.2.3.3. General Method C2
##STR00032##
[0889] An aqueous 10 M aqueous KOH solution (15 eq.) is added to a
solution of imidazo[1,2-b]pyridazin-3-yl formamide or
imidazo[1,2-a]pyrazin-3-yl formamide derivative (1 eq.) in MeOH.
The reaction mixture is stirred at r.t. until completion, then
quenched with brine and MeOH is removed in vacuo. The remaining
aqueous phase is extracted with DCM three times. The combined
organic layers are washed with brine, dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford the expected
intermediate. If the product is precipitated after addition of
brine, the following work up is used: the reaction mixture is
filtered. The solid is washed with water and dried in vacuo to
afford the expected intermediate.
1.2.3.4. Illustrative Synthesis of Intermediate Gen-3-b:
(6-Bromo-2-ethyl-imidazo[1,2-a]pyrazin-3-yl)-methyl-amine
##STR00033##
[0891] An aqueous 10 M aqueous KOH solution (28.92 mL, 289.2 mmol,
15 eq.) is added to a solution of Intermediate Gen-2-b (5.46 g,
19.2 mmol, 1 eq.) in MeOH (27.5 mL). The reaction mixture is
stirred at r.t. for 1 h, then quenched with brine (100 mL). The
reaction mixture is filtered. The solid is washed with water and
dried in vacuo to afford Intermediate Gen-3-b.
[0892] LC-MS: MW (calcd): 254 (.sup.79Br), 256 (.sup.81Br); m/z
(obsd): 255 (.sup.79Br M+H), 257 (.sup.81Br M+H)
1.2.4. General Methods D1, D2: Synthesis of Intermediate Gen-4
##STR00034##
[0893] 1.2.4.1. General Method D1
##STR00035##
[0894] Step i)
[0895] To a suspension of imidazo[1,2-b]pyridazin-3-ylamine or
imidazo[1,2-a]pyrazin-3-ylamine derivative (1 eq.) in DCM is added
TEA (4.5 eq.). The mixture is stirred for 20 to 30 min at r.t. then
Fmoc-isothiocyanate (1.12 to 2.2 eq.) is added. The resulting
solution is stirred at r.t. for 3 h to overnight. If after stirring
overnight the reaction is not complete, additional
Fmoc-isothiocyanate (0.3 to 0.5 eq.) is then introduced and
stirring is continued for 3 h to 4 h. Piperidine (3 to 3.2 eq.) is
then introduced and the reaction mixture is stirred at r.t. until
completion. Water is added to the solution and the layers are
separated. The aqueous layer is extracted with DCM, the combined
organic layers are washed with brine, dried over Na.sub.2SO.sub.4
and concentrated in vacuo. The expected product is obtained either
by chromatography on silica gel or crystallization to afford the
corresponding thiourea.
Step ii)
[0896] The above prepared thiourea (1 eq.) is added to a solution
of the corresponding bromo acetophenone derivative Gen-8 (or
commercially available products) (1.3 eq.) in EtOH. The reaction
mixture is stirred at reflux for 1 h to 3 h then concentrated in
vacuo. The expected product is obtained either by chromatography on
silica gel or crystallization to afford the Intermediate Gen-4.
1.2.4.2. Illustrative Synthesis of Intermediate Gen-4-a:
(6-Bromo-2-ethyl-imidazo[1,2-b]pyridazin-3-yl)-[4-(4-fluoro-phenyl)-thiaz-
ol-2-yl]-methyl-amine
##STR00036##
[0897] Step i)
[0898] To a suspension of
(6-Bromo-2-ethyl-imidazo[1,2-b]pyridazin-3-yl)-methyl-amine
(Gen-3-a) (17.28 g, 52.7 mmol, 1 eq.) in DCM (400 mL) is added TEA
(30.5 mL, 219 mmol, 4.5 eq.). The mixture is stirred for 30 min at
r.t. then Fmoc-isothiocyanate (32.6 g, 116 mmol, 2.2 eq.) is added.
The resulting solution is stirred at r.t. overnight. The reaction
is not complete, additional Fmoc-isothiocyanate (3.99 g, 14.17
mmol, 0.5 eq.) is then introduced and stirring is continued for 3
h. Piperidine (15.65 mL, 158 mmol, 3 eq.) is then introduced and
the reaction mixture is stirred at r.t. for 3 h. Water is added to
the solution and the layers are separated. The aqueous layer is
extracted with DCM. The combined organic layers are washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. DIPE
is added to the residue and stirred at r.t. overnight, the formed
crystals are filtered off to afford the corresponding thiourea.
[0899] LC-MS: MW (calcd): 313 (.sup.79Br), 315 (.sup.81Br); m/z MW
(obsd): 314 (.sup.79Br M+H), 316 (.sup.81Br M+H)
Step ii)
[0900] The above prepared thiourea (14.15 g, 45 mmol, 1 eq.) is
added to a solution of 2-bromo-4'-fluoroacetophenone (12.71 g, 58.5
mmol, 1.3 eq.) in EtOH (300 mL). The reaction mixture is stirred at
reflux for 1 h then concentrated in vacuo. The crude product is
stirred at r.t. in DIPE overnight, the resulting solid is separated
by filtration to afford Intermediate Gen-4-a as hydrobromide
salt.
[0901] LC-MS: MW (calcd): 431 (.sup.79Br), 433 (.sup.81Br); m/z MW
(obsd): 432 (.sup.79Br M+H), 434 (.sup.81Br M+H)
1.2.4.3. General Method D2
##STR00037##
[0903] To a solution of imidazo[1,2-b]pyridazin-3-ylamine or
imidazo[1,2-a]pyrazin-3-ylamine derivative (1 eq.) and the halogeno
heteroaryl derivative Gen-9 (or commercially available products)
(1.1 to 1.2 eq.) in THF under argon is added NaH (60% in oil
suspension, 3 eq.). The reaction mixture is heated at 90.degree. C.
until completion then cooled to r.t. After cooling to r.t. the
mixture is slowly quenched by addition of water and then diluted
with EtOAc. The organic layer is separated and the aqueous layer is
extracted with EtOAc. The combined organic layers are washed with
water and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue is purified by chromatography on
silica gel or by crystallization to deliver the expected
intermediate.
1.2.4.4. Illustrative Synthesis of Intermediate Gen-4-d:
2-[(6-Bromo-2-ethyl-imidazo[1,2-a]pyrazin-3-yl)-methyl-amino]-4-(4-fluoro-
-phenyl)-thiazole-5-carbonitrile
##STR00038##
[0905] To a solution of intermediate
(6-Bromo-2-ethyl-imidazo[1,2-a]pyrazin-3-yl)-methyl-amine (Gen-3-b)
(1.4 g, 255.12 mmol, 1 eq.) and the chlorothiazole Gen-12-a (1.57
g, 238.67 mmol, 1.2 eq.) in THF (17.5 mL) under argon is added NaH
(60% in oil suspension, 658 mg, 16.4 mmol, 3 eq.). The reaction
mixture is heated at 90.degree. C. for 3 h. After cooling to r.t.
the mixture is slowly quenched by addition of water (10 mL) and
then diluted with EtOAc. The organic layer is separated and the
aqueous layer is extracted with EtOAc. The combined organic layers
are washed with water and brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The solid is triturated for 1 h
in EtOH (14 mL), filtered off, washed with EtOH (7 mL) twice,
heptane (7 mL) and dried in vacuo to afford Intermediate
Gen-4-d.
[0906] LC-MS: MW (calcd): 456 (.sup.79Br), 458 (.sup.81Br); m/z MW
(obsd): 457 (.sup.79Br M+H), 459 (.sup.81Br M+H)
1.2.5. General Methods E, D1, D2 and D3: Synthesis of Intermediate
Gen-5
##STR00039##
[0907] 1.2.5.1. General Methods E1
##STR00040##
[0908] 1.2.5.1.1. General Method E1a
[0909] To a solution of the
6-halo-imidazo[1,2-b]pyridazin-3-ylamine or
6-halo-imidazo[1,2-a]pyrazin-3-ylamine derivative derivative (1
eq.) in toluene under argon are successively added the
corresponding amine (5 eq.), sodium tert-butoxide (2 eq.), and then
JohnPhos (0.13 eq.) and Pd.sub.2(dba).sub.3 (0.1 eq.). The reaction
mixture is heated at 115.degree. C. until completion. After cooling
to r.t., the crude product is filtered on Celpure.RTM. P65, the
cake is washed with EtOAc. Alternatively, the filtrate is washed
with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo, or the filtrate is concentrated in vacuo. The crude
product is purified by chromatography on silica gel to afford the
expected intermediate.
1.2.5.1.2. Illustrative Synthesis of Compound 1:
2-((2-ethyl-6-(piperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)(methyl)amino)-4-
-(4-fluorophenyl)thiazole-5-carbonitrile
##STR00041##
[0911] To a solution of the Intermediate Gen-4-d (1.73 g, 3.79
mmol, 1 eq.) in toluene (35 mL) under argon are successively added
piperazine (1.63 g, 18.9 mmol, 5 eq.), sodium tert-butoxide (729
mg, 7.58 mmol, 2 eq.), and then JohnPhos (147 mg, 0.49 mmol, 0.13
eq.) and Pd.sub.2(dba).sub.3 (348 mg, 0.38 mmol, 0.1 eq.). The
reaction mixture is heated at 115.degree. C. for 2 h. After cooling
to r.t., the crude product is filtered on Celpure.RTM. P65, the
cake is washed with EtOAc, and the filtrate is concentrated in
vacuo. The crude product is purified by chromatography on silica
gel (elution DCM/MeOH/NH.sub.3: 100/0/0 to 100/7/1) to afford
Compound 1.
[0912] LC-MS: MW (calcd): 462; m/z MW (obsd): 463 (M+H)
1.2.5.1.3. General Method E1b
[0913] To a solution of the
6-halo-imidazo[1,2-b]pyridazin-3-ylamine or
6-halo-imidazo[1,2-a]pyrazin-3-ylamine derivative (1 eq.) in
toluene under argon are successively added the corresponding amine
(1.1 to 1.6 eq.), sodium tert-butoxide (1.18 to 2 eq.), and then
XantPhos or DavePhos (0.1 to 0.15 eq.) and Pd.sub.2(dba).sub.3 or
PdCl.sub.2(dppf).sub.2 (0.05 to 0.056 eq.). The reaction mixture is
heated at 90.degree. C. until completion. After cooling to r.t.,
the crude product is filtered on Celite, the residue is washed with
EtOAc and the filtrate is concentrated in vacuo. Water and EtOAc
are added to the residue, the layers are separated, and the aqueous
layer is extracted with EtOAc, the combined organic layers are
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. The crude product is purified by chromatography on silica
gel or preparative LC-MS to afford the expected intermediate.
1.2.5.1.4. Illustrative Synthesis of Compound 79:
[6-(1,1-Dioxothiomorpholin-4-yl)-2-ethyl-imidazo[1,2-b]pyridazin-3-yl]-[4-
-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine
##STR00042##
[0915] To a solution of intermediate
(6-Bromo-2-ethyl-imidazo[1,2-b]pyridazin-3-yl)-[4-(4-fluoro-phenyl)-thiaz-
ol-2-yl]-methyl-amine (Gen-4-a) (100 mg, 0.231 mmol, 1 eq.) in
toluene (2 mL) under argon are successively added thiomorpholine
1,1-dioxide (47 mg, 0.347 mmol, 1.5 eq.), sodium tert-butoxide (33
mg, 0.347 mmol, 1.5 eq.), and then DavePhos (14 mg, 0.035 mmol,
0.15 eq.) and Pd.sub.2(dba).sub.3 (11 mg, 0.012 mmol, 0.05 eq.).
The reaction mixture is heated at 90.degree. C. for 1.75 h. After
cooling to r.t., the crude product is filtered on Celite, the
residue is washed with EtOAc and the filtrate is concentrated in
vacuo. To the residue water and EtOAc are added, the layers are
separated, and the aqueous layer is extracted with EtOAc, the
combined organic layers are washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product is
purified by preparative LC-MS to afford Compound 79.
[0916] LC-MS: MW (calcd): 486; m/z MW (obsd): 487 (M+H)
1.2.5.2. General Method E2
##STR00043##
[0918] To a solution of 6-halo-imidazo[1,2-b]pyridazin-3-ylamine or
6-halo-imidazo[1,2-a]pyrazin-3-ylamine derivative (1 eq.) in a
mixture dioxane/water 9/1 under argon are successively added sodium
carbonate or cesium fluoride (2 to 4 eq.), the corresponding
boronic ester (1.2 to 1.5 eq.), and then Pd(PPh.sub.3).sub.4 or
Pd(amphos)Cl.sub.2 or PdCl.sub.2dppf (0.05 to 0.08 eq.). The
reaction mixture is heated between 85.degree. C. and 95.degree. C.
until completion. After cooling to r.t., the crude product is
filtered on Clarcel and the filtrate is concentrated in vacuo.
Alternatively water and EtOAc are added to the reaction mixture,
the layers are separated, and the aqueous layer is extracted again
with EtOAc. The combined organic layers are washed with brine,
dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue
is purified by chromatography on silica gel to afford the expected
intermediate.
1.2.5.3. Illustrative Synthesis of Compound 193: tert-butyl
4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate
##STR00044##
[0920] To a solution of the
(6-Bromo-2-ethyl-imidazo[1,2-b]pyridazin-3-yl)-[4-(4-fluoro-phenyl)-thiaz-
ol-2-yl]-methyl-amine (Gen-4-a) (150.0 mg, 0.35 mmol, 1 eq.) in a
mixture dioxane/water 9/1 (3.6 mL/0.4 mL) under argon are
successively added sodium carbonate (265 mg, 1.39 mmol, 4 eq.),
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine--
1-carboxylic acid tert-butyl ester (161 mg, 0.52 mmol, 1.5 eq.),
and then Pd(PPh.sub.3).sub.4 (20 mg, 0.02 mmol, 0.05 eq.). The
reaction mixture is heated at 90.degree. C. for 3 h. After cooling
to r.t., water and EtOAc are added and the layers are separated,
the aqueous layer is further extracted with EtOAc. The combined
organic layers are washed with brine, dried over Na.sub.2SO.sub.4
and concentrated in vacuo. The residue is purified by
chromatography on silica gel (elution with Heptane/EtOAc: 100/0 to
40/60) to afford Compound 193.
[0921] LC-MS: MW (calcd): 534; m/z MW (obsd): 535 (M+H)
1.2.5.4. General Method E3
##STR00045##
[0923] To a solution of 6-halo-imidazo[1,2-b]pyridazin-3-ylamine or
6-halo-imidazo[1,2-a]pyrazin-3-ylamine derivative (1 eq.) in DMA
under argon are successively added the copper (I) iodide (0.25
eq.), PdCl.sub.2dppf (0.1 eq.), and a solution of the corresponding
organozinc compound (1.3 to 1.4 eq.) in DMA. The reaction mixture
is heated at 80.degree. C. for 1 h to 3 h. After cooling to r.t.,
the crude product is filtered on Celpure.RTM. P65, the cake is
washed with EtOAc. The filtrate is washed with water and brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The crude product is purified by chromatography on silica gel to
afford the expected intermediate.
1.2.5.5. Illustrative Synthesis of Intermediate Gen-5-ai:
4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-im-
idazo[1,2-a]pyrazin-6-yl)-piperidine-1-carboxylic acid tert-butyl
ester
##STR00046##
[0925] To a solution of
2-[(6-Bromo-2-ethyl-imidazo[1,2-a]pyrazin-3-yl)-methyl-amino]-4-(4-fluoro-
-phenyl)-thiazole-5-carbonitrile (Gen-4-d) (650 mg, 1.42 mmol, 1
eq.) in DMA (2 mL) under argon are successively added the copper
(I) iodide (68 mg, 0.355 mmol, 0.25 eq.), PdCl.sub.2dppf (104 mg,
0.142 mmol, 0.1 eq.), and a solution of
1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide (prepared
from 4-iodo-Boc-piperidine (Corley et al. 2004)) in DMA (1M in DMA,
1.99 mL, 1.99 mmol, 1.4 eq.). The reaction mixture is heated at
80.degree. C. for 2 h. After cooling to r.t., the crude product is
filtered on Celpure.RTM. P65, the residue is washed with EtOAc and
the filtrate is washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
product is purified by chromatography on silica gel (elution
DCM/MeOH: 100/0 to 70/30) to afford the expected Intermediate
Gen-5-ai.
[0926] LC-MS: MW (calcd): 561; m/z MW (obsd): 562 (M+H)
1.2.5.6. General Method E4
##STR00047##
[0927] 1.2.5.6.1. General Method E4a
[0928] To a solution of 6-halo-imidazo[1,2-b]pyridazin-3-ylamine or
6-halo-imidazo[1,2-a]pyrazin-3-ylamine derivative (1 eq.) in MeCN
are successively added the corresponding amine Gen-10 (or
commercially available products) (1.1 to 3 eq.), and DIPEA or TEA
(0 to 6 eq). The reaction mixture is heated between 85.degree. C.
and 190.degree. C. under microwave irradiation or under
conventional heating until completion. After cooling to r.t., the
crude product is concentrated in vacuo. The residue is directly
purified by chromatography on silica gel or by preparative HPLC to
afford the expected intermediate. Alternatively, the residue may be
partionned with DCM or EtOAc and water, the organic layer is
separated, the aqueous layer is further extracted with DCM or EtOAc
twice. The combined organic layers are washed with water and brine,
dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude
product is purified by chromatography on silica gel or by
preparative HPLC to afford the expected product.
1.2.5.6.2. Illustrative Synthesis of Compound 95: ethyl
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)piperidine-4-carboxylate
##STR00048##
[0930] To a solution of
(6-Bromo-2-ethyl-imidazo[1,2-b]pyridazin-3-yl)-[4-(4-fluoro-phenyl)-thiaz-
ol-2-yl]-methyl-amine (Gen-4-a) (70 mg, 0.160 mmol, 1 eq.) in MeCN
(0.7 mL) are successively added piperidine-4-carboxylic acid ethyl
ester (51 mg, 0.320 mmol, 2 eq.), and TEA (70 .mu.L, 0.480 mmol, 3
eq). The reaction mixture is heated at 150.degree. C. under
microwave irradiation for 3 h. After cooling to r.t., the crude
product is concentrated in vacuo. The residue is purified by
chromatography on silica gel (elution DCM/MeOH: 100/0 to 98/2) to
afford Compound 95.
[0931] LC-MS: MW (calcd): 508; m/z MW (obsd): 509 (M+H)
1.2.5.6.3. General Method E4b
[0932] To a solution of 6-halo-imidazo[1,2-b]pyridazin-3-ylamine or
6-halo-imidazo[1,2-a]pyrazin-3-ylamine derivative (1 eq.) in nBuOH
are successively added the corresponding amine Gen-10 (or
commercially available products) (1.1 to 4 eq.), and DIPEA or TEA
(1.5 to 5 eq). The reaction mixture is heated between 120.degree.
C. and 140.degree. C. under microwave irradiation or under
conventional thermal conditions until completion. After cooling to
r.t., the crude product is concentrated in vacuo. The residue is
directly purified by chromatography on silica gel or by preparative
HPLC to afford the expected intermediate. Alternatively, the
residue is partionned with DCM or EtOAc and water, the organic
layer is separated, the aqueous layer is extracted with DCM or
EtOAc twice. The combined organic layers are washed with water and
brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The
crude product is purified by chromatography on silica gel or by
preparative HPLC to afford the expected intermediate
1.2.5.6.4. Illustrative Synthesis of Compound 178:
2-((6-(3-((2S,6R)-2,6-dimethylmorpholino)pyrrolidin-1-yl)-2-ethylimidazo[-
1,2-b]pyridazin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitr-
ile
##STR00049##
[0934] To a solution of intermediate
2-[(6-Bromo-2-ethyl-imidazo[1,2-b]pyridazin-3-yl)-methyl-amino]-4-(4-fluo-
ro-phenyl)-thiazole-5-carbonitrile (Gen-4-b) (64.3 mg, 0.141 mmol,
1 eq.) in nBuOH (0.5 mL) are successively added the intermediate
(2S,6R)-2,6-Dimethyl-4-pyrrolidin-3-yl-morpholine (Gen-10-u) (77.8
mg, 0.422 mmol, 3 eq.), and DIPEA (74 .mu.L, 0.422 mmol, 3 eq). The
reaction mixture is heated at 140.degree. C. overnight. After
cooling to r.t., the crude product is concentrated in vacuo, the
residue is partionned with DCM and water. The organic layer is
separated, the aqueous layer is extracted with DCM twice. The
combined organic layers are washed with water and brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product is
purified by chromatography on silica gel (elution DCM/MeOH: 100/0
to 94/6) to afford Compound 178.
[0935] LC-MS: MW (calcd): 560; m/z MW (obsd): 561 (M+H)
1.2.5.7. General Method E5
##STR00050##
[0936] 1.2.5.7.1. General Method E5a
[0937] To a solution of the boc protected amine (1 eq.) in DCM is
added TFA (in excess). The reaction mixture is stirred at r.t.
until completion. Then the reaction mixture is partitioned between
DCM and water. The aqueous layer is washed twice with DCM. A
saturated Na.sub.2CO.sub.3 solution is added to the aqueous layer
until pH reached 8-9 and is extracted with DCM twice. The combined
organic layers are then washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the
expected intermediate
1.2.5.7.2. Illustrative Synthesis of Intermediate Gen-5-aa:
[6-(3-Amino-azetidin-1-yl)-2-ethyl-imidazo[1,2-b]pyridazin-3-yl]-[4-(4-fl-
uoro-phenyl)-thiazol-2-yl]-methyl-amine
##STR00051##
[0939] To a solution of compound 154 (428 mg, 0.780 mmol, 1 eq.) in
DCM (5 mL) is added TFA (593 .mu.L, 0.780 mmol, 10 eq.). The
reaction mixture is stirred at r.t. overnight. Then the reaction
mixture is partitioned between DCM and water. The aqueous layer is
washed twice with DCM. A saturated Na.sub.2CO.sub.3 solution is
added to the aqueous layer until pH reached 8-9 and is extracted
with DCM twice. The combined organic layers are then washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to afford the Intermediate Gen-5-aa.
[0940] LC-MS: MW (calcd): 423; m/z MW (obsd): 424 (M+H)
1.2.5.7.3. General Method E5b
[0941] To a solution of the boc protected amine (1 eq.) in MeOH or
dioxane is added a HCl solution in Et.sub.2O (2 M) or dioxane (4 M)
or MeOH (1.25 M) or water (12 M) (in excess). The reaction mixture
is stirred at r.t. until completion then concentrated in vacuo to
afford the expected intermediate which is used directly in the next
step without further purification. Alternatively, the residue is
partitioned between EtOAc and a saturated Na.sub.2CO.sub.3 solution
(until pH reached 8-9) and further extraction with EtOAc is
performed. The combined organic layers are then washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
afford the expected intermediate.
1.2.5.7.4. Illustrative Synthesis of Intermediate Gen-5-f:
{6-[4-(2-Amino-ethyl)-piperazin-1-yl]-2-ethyl-imidazo[1,2-b]pyridazin-3-y-
l}-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine
##STR00052##
[0943] To a solution of compound 56 (190 mg, 0.327 mmol, 1 eq.) in
MeOH (3 mL) is added a 4 M HCl solution in dioxane (2 mL). The
reaction mixture is stirred at r.t. for 20 h then concentrated in
vacuo to afford Intermediate Gen-5-f as a hydrochloride salt.
[0944] LC-MS: MW (calcd): 480; m/z MW (obsd): 481 (M+H)
1.2.5.8. General Method E6
##STR00053##
[0946] To a solution of imidazo[1,2-b]pyridazin-3-ylamine or
imidazo[1,2-a]pyrazin-3-ylamine derivative (1 eq.) in a mixture
THF/MeOH or EtOH/EtOAc with AcOH (0 to 0.05 eq.) is added PtO.sub.2
(15 to 40%) or Pd/C (10 to 20%). The flask is evacuated and
backfilled with argon. Then the reaction is evacuated and
backfilled with H.sub.2 and stirred at r.t. under atmospheric
pressure until completion, several addition of catalyst might be
required to get complete conversion. The crude product is filtered
through a pad of Clarcel and washed with MeOH or EtOH/EtOAc. The
filtrate is concentrated under reduced pressure. The residue is
purified to chromatography on silica gel to afford the expected
compound or the residue is partitioned between DCM, a saturated
Na.sub.2CO.sub.3 solution and water and further extraction with DCM
is performed. The combined organic layers are then washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to afford the expected intermediate.
1.2.5.9. Illustrative Synthesis of Intermediate Gen-5-k:
(2-Ethyl-6-piperidin-4-yl-imidazo[1,2-b]pyridazin-3-yl)-[4-(4-fluoro-phen-
yl)-thiazol-2-yl]-methyl-amine
##STR00054##
[0948] To a solution of the intermediate
[2-Ethyl-6-(1,2,3,6-tetrahydro-pyridin-4-yl)-imidazo[1,2-b]pyridazin-3-yl-
]-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine (Gen-5-a) (300
mg, 0.637 mmol, 1 eq.) in a mixture THF/MeOH (10 mL/6 mL) is added
PtO.sub.2 (60 mg, 0.264 mmol, 40%). The flask is evacuated and
backfilled with argon, then the reaction is evacuated and
backfilled with H.sub.2 and stirred at r.t. under atmospheric
pressure for 18 h. Then PtO.sub.2 (15 mg, 0.066 mmol, 10%) is
added, the flask is evacuated and backfilled with argon, then the
reaction is evacuated and backfilled with H.sub.2 and stirred at
r.t. under atmospheric pressure for 24 h. Then PtO.sub.2 (7.5 mg,
0.033 mmol, 5%) is added, the flask is evacuated and backfilled
with argon, then the reaction is evacuated and backfilled with
H.sub.2 and stirred at r.t. under atmospheric pressure for 7 h.
Then PtO.sub.2 (7.5 mg, 0.033 mmol, 5%) is added, the flask is
evacuated and backfilled with argon, then the reaction is evacuated
and backfilled with H.sub.2 and stirred at r.t. under atmospheric
pressure overnight. The crude product is filtered through a pad of
Clarcel, washed with MeOH and the filtrate is concentrated under
reduced pressure. The residue is partitioned between DCM, a
saturated Na.sub.2CO.sub.3 solution and water and further
extraction with DCM is performed. The combined organic layers are
then washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to afford Intermediate Gen-5-k.
[0949] LC-MS: MW (calcd): 436; m/z MW (obsd): 437 (M+H)
1.2.5.10. General Method E7
##STR00055##
[0951] To a solution of the alcohol (1 eq.) in DCM is added
Dess-Martin periodinane (1.5 to 4 eq.), the reaction mixture is
stirred at r.t. overnight. Then the solid is filtered and the
filtrate is concentrated in vacuo, the crude is purified by
chromatography on silica gel to afford the expected compound.
Alternatively the reaction mixture is quenched with water and a
saturated NaHCO.sub.3 solution then diluted with DCM, the aqueous
layer is extracted with a mixture of DCM twice, the combined
organic layers are washed with a saturated NaHCO.sub.3 solution, a
10% Na.sub.2S.sub.2O.sub.3 solution and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
is purified by chromatography on silica gel to afford the expected
compound.
1.2.5.11. Illustrative Synthesis of Compound 172:
2-((2-ethyl-6-(3-oxopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)-
amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile
##STR00056##
[0953] To a solution of compound 171 (40 mg, 0.086 mmol, 1 eq.) in
DCM (3 mL) is added Dess-Martin periodinane (146 mg, 0.345 mmol, 4
eq.), the reaction mixture is stirred at r.t. overnight. The
reaction mixture is quenched with water and a saturated NaHCO.sub.3
solution then diluted with DCM, the aqueous layer is extracted with
a mixture of DCM twice, the combined organic layers are washed with
a saturated NaHCO.sub.3 solution, a 10% Na.sub.2S.sub.2O.sub.3
solution and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue is purified by chromatography on
silica gel (elution DCM/MeOH: 100/0 to 96/4) to afford the expected
Compound 172.
[0954] LC-MS: MW (calcd): 461; m/z MW (obsd): 462 (M+H)
1.2.5.12. General Method E8
##STR00057##
[0956] To a solution of amino derivative (1 eq.) in MeCN or DMF or
n-BuOH are added potassium carbonate (2 to 3 eq.) or TEA (5 eq.) or
DIPEA (2 eq.), halogenated derivative Gen-11 (or commercially
available products) (1.5 to 4 eq.) and NaI (0 to 0.1 eq.). The
reaction mixture is heated in thermic or microwave conditions
between 70.degree. C. to 170.degree. C. for 1.5 h to 12 h then
cooled to r.t. The reaction mixture is quenched with water and
diluted with EtOAc. The aqueous layer is extracted with EtOAc. The
combined organic layers are washed with water and brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The residue is purified
by chromatography on silica gel to deliver the expected compound.
If the product is precipitated in the reaction mixture the
following work up is used: after cooling to r.t., the reaction
mixture is filtered. The solid is washed with MeCN, water and dried
in vacuo to afford the expected product.
1.2.5.13. Illustrative Synthesis of Compound 34:
(S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidaz-
o[1,2-b]pyridazin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanon-
e
##STR00058##
[0958] To a solution of Intermediate Gen-5-j (100 mg, 0.229 mmol, 1
eq.) in MeCN (5 mL) are added potassium carbonate (63 mg, 0.457
mmol, 2 eq), and intermediate
(S)-2-Chloro-1-(3-hydroxy-pyrrolidin-1-yl)-ethanone (Gen-11-e) (75
mg, 0.457 mmol, 2 eq.). The reaction mixture is heated at
90.degree. C. for 1.5 h then cooled to r.t, and stirred overnight.
The reaction mixture is quenched with water and diluted with EtOAc.
The aqueous layer is extracted with EtOAc. The combined organic
layers are washed with water and brine, dried over Na.sub.2SO.sub.4
and concentrated in vacuo. The residue is purified by
chromatography on silica gel (elution with DCM/MeOH: 100/0 to 93/7)
to deliver the expected Compound 34.
[0959] LC-MS: MW (calcd): 564; m/z MW (obsd): 565 (M+H)
1.2.5.14. General Methods E9
1.2.5.14.1. General Method E9a
##STR00059##
[0961] To a solution of acid (1 to 1.1 eq.) in DCM or DMF are added
HOBT (1.2 eq.) and EDC.HCl (1.1 to 1.2 eq.). The reaction mixture
is stirred at r.t. for 30 to 45 min then a prepared solution of
amine (1 to 1.1 eq.) in DCM or DMF with TEA (3 eq.) is added. The
reaction mixture is stirred at r.t. until completion, then water
and a 1 M HCl solution are added, the aqueous layer is extracted
with DCM or EtOAc, the organic layer is washed with a saturated
Na.sub.2CO.sub.3 solution or water, and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
is purified by chromatography on silica gel or preparative LC-MS to
afford the expected compound.
1.2.5.14.2. Illustrative Synthesis of Compound 97:
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)-N-(2-hydroxyethyl)piperidine-4-carboxamide
##STR00060##
[0963] To a solution of Compound 96 (40 mg, 0.08 mmol, 1 eq.) in
DMF (0.5 mL) are added HOBT (14 mg, 0.1 mmol, 1.2 eq.) and EDC.HCl
(17 mg, 0.09 mmol, 1.1 eq.). The reaction mixture is stirred at
r.t. for 30 min then a prepared solution of ethanolamine (15 mg,
0.09 mmol, 1.1 eq.) in DMF with TEA (35 .mu.L, 0.25 mmol, 3 eq.) is
added. The reaction mixture is stirred at r.t. overnight, then
water and a 1 M HCl solution are added, the aqueous layer is
extracted with EtOAc, the organic layer is washed with water three
times, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue is purified by preparative LC-MS to afford
Compound 97.
[0964] LC-MS: MW (calcd): 523; m/z MW (obsd): 524 (M+H)
1.2.5.14.3. General Method E9b
##STR00061##
[0966] To a solution of amine (1 eq.) in DCM are added TEA (3 to 5
eq.) followed by acyl chloride derivative (1 to 2 eq.). The
reaction mixture is stirred at r.t. until completion, then quenched
with water and the aqueous layer is extracted with DCM twice. The
organic layer is washed with water, and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
is purified by chromatography on silica gel to afford the expected
compound.
1.2.5.14.4. Illustrative Synthesis of Compound 124:
1-(5-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethanone
##STR00062##
[0968] To a solution of intermediate
[2-Ethyl-6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-imidazo[1,2-b]pyridazin--
3-yl]-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine (Gen-5-d)
(100 mg, 0.2 mmol, 1 eq.) in DCM (4 mL) are added TEA (139 .mu.L,
0.8 mmol, 4 eq.) followed by acetyl chloride (19 .mu.L; 0.260 mmol,
1.3 eq.). The reaction mixture is stirred at r.t. overnight, then
quenched with water and the aqueous layer is extracted with DCM
twice. The organic layer is washed with water, and brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue is purified by chromatography on silica gel (elution with
DCM/MeOH: 100/0 to 98/2) to afford Compound 124.
[0969] LC-MS: MW (calcd): 505; m/z MW (obsd): 506 (M+H)
1.2.5.14.5. General Method E9c
##STR00063##
[0971] To a solution of acid (1.1 to 1.6 eq.) in DCM or DMF are
added HATU (1.1 to 1.6 eq.) and DIPEA (2.2 to 4 eq.). The reaction
mixture is stirred at r.t. for 15 min, then amine derivative (1
eq.) is added. The reaction mixture is stirred at r.t. until
completion, then water is added, the aqueous layer is extracted
with DCM or EtOAc, the organic layer is washed with brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue is purified by chromatography on silica gel or preparative
LC-MS to afford the expected compound.
1.2.5.14.6. Illustrative Synthesis of Compound 136:
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)pyrrolidin-3-yl)-2-hydroxyacetamide
##STR00064##
[0973] To a solution of hydroxy-acetic acid (26 mg, 0.34 mmol, 1.6
eq.) in DCM (2 mL) are added HATU (129 mg, 0.34 mmol, 1.6 eq.) and
DIPEA (80 .mu.L, 0.46 mmol, 2.2 eq.). The reaction mixture is
stirred at r.t. for 15 min, then Compound 134 (90 mg, 0.21 mmol, 1
eq.) is added. The reaction mixture is stirred at r.t. overnight,
then water is added, the aqueous layer is extracted with DCM. The
organic layer is washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue is purified by
chromatography on silica gel (elution with DCM/MeOH: 100/0 to 95/5)
then by preparative LC-MS to afford Compound 136.
[0974] LC-MS: MW (calcd): 495; m/z MW (obsd): 496 (M+H)
1.2.5.15. General Method E10
##STR00065##
[0976] To a solution of the appropriate amine (1.0 eq.) in MeOH are
added TEA (0 to 3 eq.), acetic acid if needed (0 to 3 eq) and the
aldehyde or ketone (1.5 to 2 eq.). The reaction mixture is stirred
at r.t. for 1 h to overnight then NaBH.sub.3CN (1.5 to 3 eq.) is
added. The reaction mixture is stirred at r.t. for 8 h to 16 h,
then concentrated in vacuo. The residue is dissolved in a mixture
of DCM and water or a saturated NaHCO.sub.3 solution, the two
phases are separated and the aqueous phase is extracted with DCM.
The combined organic layers are washed with water and brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue is purified by chromatography on silica gel to afford the
expected product.
1.2.5.16. Illustrative Synthesis of Compound 38:
N-(2-ethyl-6-(4-(oxetan-3-yl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-
-4-(4-fluorophenyl)-N-methylthiazol-2-amine
##STR00066##
[0978] To a solution of Intermediate
(2-Ethyl-6-piperazin-1-yl-imidazo[1,2-b]pyridazin-3-yl)-[4-(4-fluoro-phen-
yl)-thiazol-2-yl]-methyl-amine (Gen-5-j) (50 mg, 0.09 mmol, 1.0
eq.) in MeOH (2 mL) are added TEA (35 .mu.L, 0.27 mmol, 3 eq) and
oxetan-3-one (7.9 .mu.L, 0.135 mmol, 1.5 eq.). The reaction mixture
is stirred at r.t. for 14 h then NaBH.sub.3CN (17 mg, 0.27 mmol, 3
eq.) is added. The reaction mixture is stirred at r.t. 8 h, then
concentrated in vacuo. The residue is dissolved in a mixture of DCM
and a saturated NaHCO.sub.3 solution, the two phases are separated
and the aqueous phase is extracted with DCM. The combined organic
layers are washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
is purified by chromatography on silica gel (elution DCM/MeOH:
100/0 to 90/10) to afford Compound 38.
[0979] LC-MS: MW (calcd): 493; m/z MW (obsd): 494 (M+H)
1.2.5.17. General Method E11
##STR00067##
[0981] To a solution of the appropriate amine (1 eq.) in DCM or a
mixture of DCM/MeCN (3/1) at 0.degree. C. are added TEA (2.5 to 5
eq.) and sulfonyl chloride (1.1 to 2 eq.). The reaction mixture is
stirred at r.t. until completion. The crude product is quenched
with water and diluted with DCM, the aqueous layer is extracted
with DCM. The combined organic layers are washed with water and
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue is purified by chromatography on silica gel to
afford the expected compound.
1.2.5.18. Illustrative Synthesis of Compound 123:
N-(2-ethyl-6-(5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)im-
idazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine
##STR00068##
[0983] To a solution of intermediate
[2-Ethyl-6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-imidazo[1,2-b]pyridazin--
3-yl]-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine (Gen-5-d)
(100 mg, 0.2 mmol, 1 eq.) in DCM (6 mL) at 0.degree. C. are added
TEA (139 .mu.L, 0.8 mmol, 4 eq.) and mesyl chloride (20 .mu.L, 0.26
mmol, 1.3 eq.). The reaction mixture is stirred at r.t. for 2.5 h.
The crude product is quenched with water and diluted with DCM, the
aqueous layer is extracted with DCM. The combined organic layers
are washed with water and brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue is purified by
chromatography on silica gel (elution with DCM/MeOH: 100/0 to
100/1) to afford the expected compound 123.
[0984] LC-MS: MW (calcd): 541; m/z MW (obsd): 542 (M+H)
1.2.5.19. General Methods E12
##STR00069##
[0986] To a solution of the corresponding nucleophile (2 to 6 eq.)
in THF or a mixture of THF/MeCN (3/2) are added NaI (0.15 to 0.17
eq.) and halogenoalkyl group containing
imidazo[1,2-b]pyridazin-3-ylamine or
imidazo[1,2-a]pyrazin-3-ylamine derivative (1 eq.). The reaction
mixture is heated between 150.degree. C. and 180.degree. C. under
microwave irradiation for 1.5 h to 2 h. After cooling, the reaction
mixture is concentrated in vacuo, then the crude product is
purified by preparative LC-MS to afford the expected compound.
Alternatively the crude product is partionned between water and
DCM, the aqueous layer is extracted with DCM three times. The
combined organic layers are washed with a saturated NaHCO.sub.3
solution and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue is purified by chromatography on
silica gel to afford the expected compound.
1.2.5.20. Illustrative Synthesis of Compound 127:
N-(2-ethyl-6-(5-(3-morpholinopropylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-
-2(1H)-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-
-2-amine
##STR00070##
[0988] To a solution of morpholine (39 .mu.L, 0.447 mmol, 6 eq.) in
THF (3 mL) are added NaI (2 mg, 0.012 mmol, 0.17 eq.) and Compound
125 (45 mg, 0.074 mmol, 1 eq.). The reaction mixture is heated at
180.degree. C. under microwave irradiation for 1.5 h. After
cooling, the reaction mixture is concentrated in vacuo, then the
crude product is purified by preparative LC-MS to afford Compound
127.
[0989] LC-MS: MW (calcd): 654; m/z MW (obsd): 655 (M+H)
1.2.5.21. General Method E13
##STR00071##
[0991] To a solution of the corresponding ester (1 eq.) in a
mixture of THF/water (2/1) is added LiOH (4 to 5 eq.). The reaction
mixture is stirred at r.t. until completion, then the reaction
mixture is acidified with a 1M HCl solution. The aqueous layer is
extracted with a mixture of Et.sub.2O/EtOAc twice, the combined
organic layers are washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
is purified by chromatography on silica gel to afford the expected
product.
1.2.5.22. Illustrative Synthesis of Compound 96:
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)piperidine-4-carboxylic acid
##STR00072##
[0993] To a solution of compound 95 (70 mg, 0.14 mmol, 1 eq.) in a
mixture of THF/water (2 mL/1 mL) is added LiOH (13 mg, 0.55 mmol, 5
eq.). The reaction mixture is stirred at r.t. for 3 days, then the
reaction mixture is acidified with a 1 M HCl solution. The aqueous
layer is extracted with a mixture of Et.sub.2O/EtOAc twice, the
combined organic layers are washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
is purified by chromatography on silica gel (elution with DCM/MeOH:
98/2 to 92/8) to afford Compound 96.
[0994] LC-MS: MW (calcd): 480; m/z MW (obsd): 481 (M+H)
1.2.5.23. General Method E14
##STR00073##
[0996] To a solution of thiazole derivative (1 eq.) in THF are
added formaldehyde (in excess.), TEA (in excess) and water. The
reaction mixture is heated to 140.degree. C. under microwave
irradiation for 40 min to 16 h. The crude product mixture is
quenched with water and an aqueous NH.sub.3 solution. The aqueous
layer is extracted with EtOAc. The combined organic layers are
washed with water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The residue is purified by
chromatography on silica gel or preparative HPLC to deliver the
expected product.
1.2.5.24. Illustrative Synthesis of Compound 144:
(1-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)-
amino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)methanol
##STR00074##
[0998] To a solution of compound 143 (100 mg, 0.22 mmol, 1 eq.) in
THF (1 mL) are added aqueous formaldehyde (1.2 mL), TEA (250 .mu.L)
and water (1 mL). The reaction mixture is heated at 140.degree. C.
under microwave irradiation for 1 h. The crude product mixture is
quenched with water and a aqueous NH.sub.3 solution. The aqueous
layer is extracted with EtOAc twice. The combined organic layers
are washed with water and brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue is purified by
chromatography on silica gel (elution DCM/MeOH: 100/0 to 95/5) to
afford Compound 144.
[0999] LC-MS: MW (calcd): 482; m/z MW (obsd): 483 (M+H)
1.2.5.25. General Method E15
##STR00075##
[1001] To a solution of thiazole derivative (1 eq.) in pyridine at
0.degree. C. is slowly added trifluoroacetic anhydride (5 to 6
eq.). The reaction mixture is stirred at 0.degree. C. for 1 h then
partitioned between DCM or EtOAc and water or brine. The organic
phase is separated. The aqueous layer is extracted with DCM. The
combined organic layers are washed with water and brine, dried over
MgSO.sub.4, filtered and concentrated in vacuo. The residue is
purified by chromatography on silica gel to afford the expected
product.
1.2.5.26. Illustrative Synthesis of Intermediate Gen-5-af:
4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-5-(2,2,2-trifluoro-acetyl)-thiazol-2-y-
l]-methyl-amino}-imidazo[1,2-b]pyridazin-6-yl)-piperazine-1-carboxylic
acid tert-butyl ester
##STR00076##
[1003] To a solution of intermediate
4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,-
2-b]pyridazin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester
(Gen-5-i) (250 mg, 0.47 mmol, 1 eq.) in pyridine (5 mL) at
0.degree. C. is slowly added trifluoroacetic anhydride (328 .mu.L,
2.33 mmol, 5 eq.). The reaction mixture is stirred at 0.degree. C.
for 1 h then partitioned between EtOAc and brine, the organic phase
is separated. The aqueous layer is extracted with EtOAc twice. The
combined organic layers are washed with water and brine, dried over
MgSO.sub.4, filtered and concentrated in vacuo. The crude product
is purified by chromatography on silica gel (elution with DCM/MeOH:
100/01 to 90/10). The residue is dissolved in DCM, washed with a
saturated NaHCO.sub.3 solution and brine, dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford Intermediate
Gen-5-af.
[1004] LC-MS: MW (calcd): 633; m/z MW (obsd): 634 (M+H)
1.2.5.27. General Methods E16
##STR00077##
[1006] To a solution of thiazole derivative (1 eq.) in DCM is added
polymer-supported bromide (1.1 eq.). The mixture is stirred
vigorously at r.t. for 4 h to overnight. The crude mixture is
filtered, the residue is washed with DCM and MeOH. The filtrate is
concentrated in vacuo to afford the expected product.
1.2.5.28. Illustrative Synthesis of Intermediate Gen-5-m:
2-[4-(3-{[5-Bromo-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-
-imidazo[1,2-b]pyridazin-6-yl)-piperazin-1-yl]-N,N-dimethyl-acetamide
##STR00078##
[1008] To a solution of Compound 42 (195 mg, 0.373 mmol, 1 eq.) in
DCM (10 mL) is added polymer-supported bromide (274 mg, 0.410 mmol,
1.1 eq.). The mixture is stirred vigorously at r.t. overnight. The
crude mixture is filtered, the residue is washed with DCM and MeOH.
The filtrate is concentrated in vacuo to afford Intermediate
Gen-5-m.
[1009] LC-MS: MW (calcd): 600 (.sup.79Br), 602 (.sup.81Br); m/z MW
(obsd): 601 (.sup.79Br M+H), 603 (.sup.81Br M+H)
1.2.5.29. General Method E17
##STR00079##
[1011] To a solution of the above prepared bromide (1 eq.) in
pyridine is added copper (I) cyanide (5 eq.). The mixture is heated
at 160.degree. C. under microwave irradiation for 2 h. The crude
mixture is quenched with water, and diluted in EtOAc. The organic
layer is separated, the aqueous layer is extracted with EtOAc. The
combined organic layers are washed with water and brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The residue is purified
by chromatography on silica gel or preparative LC-MS to afford the
expected product.
1.2.5.30. Illustrative Synthesis of Compound 44:
2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylim-
idazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide
##STR00080##
[1013] To a solution of intermediate
2-[4-(3-{[5-Bromo-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-
-imidazo[1,2-b]pyridazin-6-yl)-piperazin-1-yl]-N,N-dimethyl-acetamide
(Gen-5-m) (95 mg, 0.158 mmol, 1 eq.) in pyridine (1 mL) is added
copper cyanide (71 mg, 0.790 mmol, 5 eq.). The mixture is heated at
160.degree. C. under microwave irradiation for 2 h. The crude
mixture is quenched with water, and diluted in EtOAc. The organic
layer is separated, the aqueous layer is extracted with EtOAc. The
combined organic layers are washed with water and brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The residue is purified
by chromatography on silica gel (elution DCM/MeOH: 100/0 to 90/10)
and by preparative LC-MS to afford Compound 44.
[1014] LC-MS: MW (calcd): 547; m/z MW (obsd): 548 (M+H)
1.2.5.31. General Method E18
##STR00081##
[1016] To a solution of hydroxy derivative (1 eq.) in DCM or DMF
are added imidazole (2 to 3 eq.) and a solution of TBSCl or TBDPSCl
(1.1 to 2 eq.) in DCM or DMF. The reaction mixture is stirred at
r.t. until completion. Then the reaction mixture is quenched with a
saturated Na.sub.2CO.sub.3 solution or water and diluted in DCM or
EtOAc. The organic layer is separated, the aqueous layer is
extracted with DCM or EtOAc twice. The combined organic layers are
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. The residue is purified by chromatography on silica gel to
afford the expected product. Alternatively, the residue is used
directly in the next step without purification.
1.2.5.32. Illustrative Synthesis of Intermediate Gen-5-ae:
{6-[(S)-3-(tert-Butyl-diphenyl-silanyloxymethyl)-piperazin-1-yl]-2-ethyl--
imidazo[1,2-b]pyridazin-3-yl}-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-am-
ine
##STR00082##
[1018] To a solution of compound 60 (90 mg, 0.19 mmol, 1 eq.) in
DCM (2 mL) are added imidazole (26 mg, 0.38 mmol, 2 eq.) and a
solution of TBDPSCl (59 .mu.L, 0.23 mmol, 1.2 eq.) in DCM (0.4 mL).
The reaction mixture is stirred at r.t. overnight. Then the
reaction mixture is quenched with a saturated Na.sub.2CO.sub.3
solution and diluted in DCM. The organic layer is separated, the
aqueous layer is extracted with DCM twice. The combined organic
layers are washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The residue is purified by chromatography on
silica gel (elution with DCM/MeOH: 100/0 to 90/10) to afford
Intermediate Gen-5-ae.
[1019] LC-MS: MW (calcd): 705; m/z (obsd): 706 (M+H)
1.2.5.33. General Method E19
##STR00083##
[1021] To a solution of protected hydroxy derivative (1 eq.) in THF
is added a 1M TBAF solution in THF (1 to 2 eq.), the reaction
mixture is stirred at r.t. until completion. Then the reaction
mixture is quenched with a saturated Na.sub.2CO.sub.3 solution or
water and diluted in EtOAc. The organic layer is separated, the
aqueous layer is extracted with EtOAc three times. To the combined
organic layers is added heptane, and are washed with water twice
and brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo.
The residue is purified by chromatography on silica gel or
preparative LC-MS to afford the expected product.
1.2.5.34. Illustrative Synthesis of Compound 64:
(S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidaz-
o[1,2-b]pyridazin-6-yl)-2-(hydroxymethyl)piperazin-1-yl)-1-(pyrrolidin-1-y-
l)ethanone
##STR00084##
[1023] To a solution of
2-[2-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2-ethyl-3-{[4-(4-fluoro-ph-
enyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-b]pyridazin-6-yl)-piperazin--
1-yl]-1-pyrrolidin-1-yl-ethanone (100 mg, 0.13 mmol, 1 eq.) in THF
(1.5 mL) is added a 1M TBAF solution in THF (134 .mu.L, 0.13 mmol,
1), the reaction mixture is stirred at r.t. for 1 h. Then the
reaction mixture is quenched with a saturated Na.sub.2CO.sub.3
solution and diluted in EtOAc. The organic layer is separated, the
aqueous layer is extracted with EtOAc three time. To the combined
organic layers is added heptane, and are washed with water twice
and brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo.
The residue is purified by chromatography on silica gel (elution
with DCM/MeOH: 100/0 to 93/7) to afford Compound 64.
[1024] LC-MS: MW (calcd): 578; m/z (obsd): 579 (M+H)
1.2.5.35. General Method D1
##STR00085##
[1026] Intermediates Gen-5 are prepared from intermediates Gen-7
according to general method D1 described previously.
1.2.5.36. General Method D2
##STR00086##
[1028] Intermediates Gen-5 are prepared from intermediates Gen-7
according to general method D2 described previously.
1.2.5.37. General Method D3
##STR00087##
[1029] Step i)
[1030] To a solution of imidazo[1,2-b]pyridazin-3-ylamine or
imidazo[1,2-a]pyrazin-3-ylamine derivative (1 eq.) in THF under
argon is slowly added NaH (60% in oil suspension, 3 eq.). The
reaction mixture is refluxed for 30 min then cooled to 40.degree.
C. before adding the halogeno heteroaryl derivative (1.2 eq.) in
THF, the reaction mixture is refluxed until completion. After
cooling to r.t. the mixture is slowly quenched by addition of water
and then diluted with EtOAc. The organic layer is separated and the
aqueous layer extracted with EtOAc. The combined organic layers are
washed with water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The residue is purified by
chromatography on silica gel to deliver the corresponding halogeno
derivative.
Step ii)
[1031] To a solution of the above prepared halogeno derivative (1
eq.) in a mixture of dioxane and water under argon are successively
added CsF or LiOH (2.1 to 4 eq.), the corresponding boronic ester
(1.2 to 1.5 eq.), and then Pd(amphos)Cl.sub.2 (0.05 to 0.1 eq.) or
Pd(OAc).sub.2 (0. 01 eq.) with Sphos (0.02 eq.). The reaction
mixture is heated between 80.degree. C. and 110.degree. C. until
completion. After cooling to r.t., the crude product is partionned
with water and EtOAc and the layers are separated. The aqueous
layer is extracted with EtOAc twice, the combined organic layers
are washed with brine, dried over Na.sub.2SO.sub.4 and concentrated
in vacuo. The residue is purified by chromatography on silica gel
to afford the expected intermediate.
1.2.5.38. Illustrative Synthesis of Intermediate Gen-5-aad:
4-(2-Ethyl-3-{[2-(4-fluoro-phenyl)-pyrimidin-4-yl]methyl-amino}-imidazo[1-
,2-b]pyridazin-6-yl)-piperidine-1-carboxylic acid tert-butyl
ester
##STR00088##
[1032] Step i)
[1033] To a solution of intermediate
4-(2-Ethyl-3-methylamino-imidazo[1,2-b]pyridazin-6-yl)-piperidine-1-carbo-
xylic acid tert-butyl ester (Gen-7-a) (200 mg, 0.556 mmol, 1 eq.)
in THF (2.6 mL) under argon is slowly added NaH (60% in oil
suspension, 66.8 mg, 1.669 mmol, 3 eq.). The reaction mixture is
refluxed for 30 min then cooled to 40.degree. C. then
2,4-dichloropyrimidine (99.5 mg, 0.667 mmol, 1.2 eq.) in THF (1.2
mL) is added, the reaction mixture is refluxed for 1.5 h. After
cooling to r.t. the mixture is slowly quenched by addition of water
and then diluted with EtOAc. The organic layer is separated and the
aqueous layer is extracted with EtOAc. The combined organic layers
are washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue is purified by chromatography on
silica gel (elution DCM/MeOH: 100/0 to 95/5) to deliver
4-{3-[(2-Chloro-pyrimidin-4-yl)-methyl-amino]-2-ethyl-imidazo[1,2-b]pyrid-
azin-6-yl}-piperidine-1-carboxylic acid tert-butyl ester.
[1034] LC-MS: MW (calcd): 471 (.sup.35Cl), 473 (.sup.37Cl); m/z MW
(obsd): 472 (.sup.35Cl M+H), 474 (.sup.37Cl M+H)
Step ii)
[1035] To a solution of the above prepared halogeno derivative (50
mg, 0.106 mmol, 1 eq.) in dioxane (850 .mu.L) under argon are
successively added LiOH (10.1 mg, 0.424 mmol, 4 eq.) in water (212
.mu.L), 4-fluorophenylboronic acid (17.8 mg, 0.127 mmol, 1.2 eq.),
Pd(OAc).sub.2 (0.3 mg, 0.001 mmol, 0.01 eq.) and Sphos (0.9 mg,
0.002 mmol, 0.02 eq.). The reaction mixture is heated at 80.degree.
C. for 4 h. After cooling to r.t., the crude product is partionned
with water and EtOAc and the layers are separated. The aqueous
layer is extracted with EtOAc twice, the combined organic layers
are washed with brine, dried over Na.sub.2SO.sub.4 and concentrated
in vacuo. The residue is purified by chromatography on silica gel
(elution DCM/MeOH: 100/0 to 90/10) to afford Intermediate
Gen-5-aad.
[1036] LC-MS: MW (calcd): 531; m/z MW (obsd): 532 (M+H)
1.2.6. General Methods E: Synthesis of Intermediate Gen-6
##STR00089##
[1038] Intermediates Gen-6 are prepared from Intermediates Gen-2
according to one or several general methods E described
previously.
1.2.7. General Methods C2: Synthesis of Intermediate Gen-7
##STR00090##
[1040] Intermediates Gen-7 are prepared from Intermediates Gen-6
according to general method C2 described previously.
1.2.8. General Method G1: General Synthesis of
.alpha.-halogenoketones Gen-8
##STR00091##
[1042] To a solution of ketone (1 eq.) in MeCN is added
phenyltrimethylammonium tribromide (1 eq.). The resulting mixture
is stirred at r.t. for 3 h, and then is concentrated in vacuo. The
organic residue is dissolved in EtOAc and the organic layer is
washed with water, with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to give the Intermediate Gen-8.
The crude product is used directly in the next step without
purification
1.2.9. Illustrative Synthesis of Intermediate Gen-8-a:
2-(2-Bromo-acetyl)-5-fluoro-benzonitrile
##STR00092##
[1043] Step i)
[1044] To a solution of 1-(2-Bromo-4-fluoro-phenyl)-ethanone (3.0
g, 13.82 mmol, 1 eq.) in DMA (150 mL) under argon is added
Zn(CN).sub.2 (1.6 g, 13.82 mmol, 1 eq.), Pd.sub.2(dba).sub.3 (1.26
g, 1.38 mmol, 0.1 eq.), dppf (1.53 g, 2.76 mmol, 0.2 eq.) and Zn
dust (107.8 mg, 1.65 mmol, 0.12 eq.). The reaction mixture is
heated at 100.degree. C. for 1.4 h, after cooling to r.t. the
mixture is slowly quenched by addition of water and then diluted
with EtOAc. The organic layer is separated and the aqueous layer
extracted with EtOAc twice. The combined organic layers are washed
with water, dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. The residue is purified either by chromatography on
silica gel to afford the expected product.
[1045] LC-MS: MW (calcd): 163; m/z MW (obsd): 164 (M+H)
Step ii)
[1046] To a solution of 2-acetyl-5-fluoro-benzonitrile (1.52 g,
9.33 mmol, 1 eq.) in MeCN (40 mL) is added phenyltrimethylammonium
tribromide (3.51 g, 1 eq.). The resulting mixture is stirred at
r.t. for 3 h, and then is concentrated in vacuo. The organic
residue is dissolved in EtOAc and the organic layer is washed with
water, with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give the Intermediate Gen-8-a. The crude
is used directly in the next step without purification
[1047] LC-MS: MW (calcd): 241 (.sup.79Br), 243 (.sup.81Br); m/z MW
(obsd): 242 (.sup.79Br M+H), 244 (.sup.81Br M+H)
1.2.10. General Method G2: General Synthesis of Intermediates
Gen-9
1.2.10.1. General Method G2a
##STR00093##
[1048] Step i)
[1049] To a solution of benzoylacetonitrile derivative (1 eq.) in
EtOH is added pyridine (1 eq.). The resulting mixture is stirred at
70.degree. C. for 15 min then cooled at r.t. A previously stirred
suspension of thiourea (2 eq.) and iodine (1 eq.) in EtOH is then
slowly added. After 1 h at r.t. a cold 1 M Na.sub.2S.sub.2O.sub.3
solution is added under stirring. The resulting precipitate is
filtered, washed with water, and finally dried under vacuo to
afford the amino-4-phenyl-thiazole-5-carbonitrile derivative.
Step ii)
[1050] To a solution of copper (II) chloride (1.2 eq.) in MeCN is
added dropwise tert-butyl nitrite (1.5 eq). After stirring at r.t.
for 30 min, the amino-4-phenyl-thiazole-5-carbonitrile (1 eq.) is
introduced portionwise and stirring is continued for 1 h. The
reaction mixture is then carefully quenched by addition of a 1 M
HCl solution. After 15 min stirring, the organic phase is
separated; the aqueous phase is further extracted with EtOAc. The
combined organic layers are washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
product product is filtered on a silica plug and eluted with DCM.
Solvents are evaporated and the residue is finally triturated in
heptane, filtered and dried to give Intermediate Gen-9.
1.2.10.2. Illustrative Synthesis of Intermediate Gen-9-a:
2-Chloro-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile
##STR00094##
[1051] Step i)
[1052] To a solution of 4-fluorobenzoylacetonitrile (50 g, 306
mmol, 1 eq.) in EtOH (600 mL) is added pyridine (24.7 mL, 306 mmol,
1 eq.). The resulting mixture is stirred at 70.degree. C. for 15
min then cooled to r.t. A previously stirred suspension of thiourea
(46.7 g, 613 mmol, 2 eq.) and iodine (77.8 g, 306 mmol, 1 eq.) in
EtOH (300 mL) is then slowly added. After 1 h at r.t. a cold 1 M
Na.sub.2S.sub.2O.sub.3 solution (360 mL) is added under stirring.
The resulting precipitate is filtered, washed with water, and
finally dried under vacuo to afford
2-Amino-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile.
[1053] .sup.1H NMR .delta. (ppm) (400 MHz, DMSO): 8.26 (2 H, s),
7.97 (2 H, dd), 7.36 (2 H, t)
Step ii)
[1054] To a solution of copper (II) chloride (36.8 g, 273 mmol, 1.2
eq.) in MeCN (500 mL) is added dropwise tert-butyl nitrite (40.7
mL, 342 mmol, 1.5 eq). After stirring at r.t. for 30 min, amine
previously obtained in step i (50 g, 228 mmol, 1 eq.) is introduced
portionwise and stirring is continued for 1 h. The reaction mixture
is then carefully quenched by addition of a 1 M HCl solution (750
mL). After 15 min stirring, the organic phase is separated, the
aqueous phase is further extracted with EtOAc. The combined organic
layers are washed with brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The crude product product is filtered on
a silica plug (250 g) and eluted with DCM. Solvents are evaporated
and the residue is finally triturated in heptane, filtered and
dried to afford Intermediate Gen-9-a.
[1055] .sup.1H NMR .delta. (ppm) (400 MHz, DMSO): 8.06 (2 H, dd),
7.46 (2 H, dd)
1.2.10.3. General Method G2b
##STR00095##
[1057] To a solution of the halogenoheterocycle derivative (1 eq.)
in a mixture of dioxane/water (9/1) or MeCN/water (3/1) under argon
are successively added the corresponding boronic ester (1 to 1.2
eq.), CsF (2.1 eq.) and Pd(amphos)Cl.sub.2 (0.05 eq.) or
Na.sub.2CO.sub.3 (3 eq.), and Pd(PPh.sub.3).sub.4 (0.1 eq.). The
reaction mixture is heated between 90.degree. C. and 110.degree. C.
until completion. After cooling to r.t., the crude product is
partionned between water and EtOAc and the layers are separated.
The aqueous layer is extracted with EtOAc twice, the combined
organic layers are washed with brine, dried over Na.sub.2SO.sub.4
and concentrated in vacuo. The residue is purified by
chromatography on silica gel to afford the expected
intermediate.
1.2.10.4. Illustrative Synthesis of Intermediate Gen-9-d:
5-Fluoro-2-(6-fluoro-pyridin-2-yl)-benzonitrile
##STR00096##
[1059] To a solution of the 2-chloro-6-fluoropyridine (400 mg,
3.041 mmol, 1 eq.) in a mixture of dioxane (9 mL)/water (1 mL)
under argon are successively added
5-Fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile
(901.6 mg, 3.649 mmol, 1.2 eq.), CsF (970 mg, 3.041 mmol, 2.1 eq.)
and Pd(amphos)Cl.sub.2 (107.7 mg, 0.152 mmol, 0.05 eq.). The
reaction mixture is heated at 110.degree. C. for 2.5 h. After
cooling to r.t., the crude product is partionned between water and
EtOAc and the layers are separated. The aqueous layer is extracted
with EtOAc twice, the combined organic layers are washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The
residue is purified by chromatography on silica gel (elution
heptanes/EtOAc (100/0 to 80/20) to afford Intermediate Gen-9-d.
[1060] LC-MS: MW (calcd): 216; m/z MW (obsd): 217 (M+H)
1.2.11. General Method G3: General Synthesis of Intermediate
Gen-10
##STR00097##
[1061] 1.2.11.1. General Method G3a
##STR00098##
[1062] Step i)
[1063] To a solution of the appropriate amine (2.0 to 3.3 eq.) in
MeOH or DCE are added acetic acid if needed (0 to 3 eq) and the
aldehyde or ketone (1 eq.). The reaction mixture is stirred at r.t.
for 1 h to overnight then NaBH.sub.3CN (1.5 to 4 eq.) or
NaBH(OAc).sub.3 (5 eq.) is added. The reaction mixture is stirred
at r.t. for 8 h to 16 h, then concentrated in vacuo. The residue is
dissolved in a mixture of DCM and a 1 M NaOH solution or a
saturated NaHCO.sub.3 solution, the two phases are separated and
the aqueous phase is extracted with DCM. The combined organic
layers are washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
is purified by chromatography on silica gel to afford the expected
product.
Step ii)
[1064] To a solution of the boc protected amine (1 eq.) in MeOH or
dioxane is added a HCl solution in Et.sub.2O (2 M) or dioxane (4 M)
or MeOH (1.25 M) or water (12 M) (in excess). Alternatively, to a
solution of the boc protected amine (1 eq.) in DCM is added TFA (in
excess). The reaction mixture is stirred at r.t. until completion
then concentrated in vacuo. The residue is partitioned between
EtOAc or DCM and a saturated Na.sub.2CO.sub.3 solution (until pH
reached 8-9) and further extraction with EtOAc is performed. The
combined organic layers are then washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the
expected intermediate. Alternatively, the reaction mixture is
concentrated in vacuo, and the crude product is used directly in
the next step as hydrochloride salt without purification.
1.2.11.2. Illustrative Synthesis of Intermediate Gen-10-u:
(2S,6R)-2,6-Dimethyl-4-pyrrolidin-3-yl-morpholine
##STR00099##
[1065] Step i)
[1066] To a solution of cis-2,6-dimethylmorpholine (0.22 mL, 1.782
mmol, 3.3 eq.) in DCE (9 mL) is added N-boc-3-pyrrolidinone (100
mg, 0.539 mmol, 1 eq.). The reaction mixture is stirred at r.t.
then NaBH(OAc).sub.3 (572.1 mg, 2.699 mmol, 5 eq.) is added. The
reaction mixture is stirred at r.t. overnight, then concentrated in
vacuo. The residue is partionned between DCM and a saturated
NaHCO.sub.3 solution, the two phases are separated and the aqueous
phase is extracted with DCM twice. The combined organic layers are
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue is purified by chromatography on
silica gel (elution Heptane/EtOAc: 50/50 to 0/100) to afford the
expected product.
[1067] LC-MS: MW (calcd): 284; m/z MW (obsd): 285 (M+H)
Step ii)
[1068] To a solution of the above boc protected amine (120 mg,
0.422 mmol, 1 eq.) in dioxane (1 mL) is added a 4 M HCl solution in
dioxane (0.85 mL). The reaction mixture is stirred at r.t.
overnight then concentrated in vacuo, to afford Intermediate
Gen-10-u as hydrochloride salt which used directly in the next step
without purification.
[1069] LC-MS: MW (calcd): 184; m/z MW (obsd): 185 (M+H)
1.2.11.3. General Method G3b
##STR00100##
[1070] Step i)
[1071] To a solution of acid (1 to 1.1 eq.) in DCM or THF or a
mixture THF/DCM are added HOBT (1.2 to 1.5 eq.) and EDC.HCl (1.2 to
1.5 eq.) or TBTU (1.1 eq.). The reaction mixture is stirred at r.t.
for 30 to 45 min then a prepared solution of amine (1 to 1.1 eq.)
in DCM or DMF with TEA (3 eq.) is added. The reaction mixture is
stirred at r.t. until completion, then water and a 1 M HCl solution
are added, the aqueous layer is extracted with DCM or EtOAc, the
organic layer is washed with a saturated Na.sub.2CO.sub.3 solution
or water, and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue is purified by chromatography on
silica gel or preparative LC-MS to afford the expected product.
[1072] Or to a solution of amine (1 eq.) in DCM or MeCN are added
TEA (0 to 2 eq.) followed by acyl chloride derivative (1 to 1.11
eq.). The reaction mixture is stirred at r.t. until completion,
then is quenched with water and the aqueous layer is extracted with
DCM or EtOAc twice. The organic layer is washed with water, and
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue is purified by chromatography on silica gel to
afford the expected product.
Step ii)
[1073] Intermediates Gen-10 are prepared from the above boc
protected amine in step i according to step ii of general method
G3a.
1.2.11.4. Illustrative Synthesis of Intermediate Gen-10-f:
Pyrrolidine-3-carboxylic acid (2-hydroxy-ethyl)-amide
##STR00101##
[1074] Step i)
[1075] To a solution of pyrrolidine-1,3-dicarboxylic acid
1-tert-butyl ester (200 mg, 0.929 mmol, 1 eq.) in THF/DCM (2 mL/3
mL) are added HOBT (188 mg, 0.394 mmol, 1.5 eq.) and EDC.HCl (267
mg, 1.394 mmol, 1.5 eq.). The reaction mixture is stirred at r.t.
for 45 min then a prepared solution of ethanolamine (84 .mu.L,
1.394 mmol, 1.5 eq.) in DCM is added. The reaction mixture is
stirred at r.t. for 2 h, then water and a 1 M HCl solution are
added, the aqueous layer is extracted with DCM, the organic layer
is washed with a saturated Na.sub.2CO.sub.3 solution or water, and
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to afford the expected product.
Step ii)
[1076] To a solution of the above boc protected amine (150 mg,
0.437 mmol, 1 eq.) in MeOH (2 mL) is added a 4 M HCl solution in
dioxane (2 mL). The reaction mixture is stirred at r.t. overnight
then concentrated in vacuo, to afford Intermediate Gen-10-f as
hydrochloride salt which used directly in the next step without
purification.
1.2.11.5. Illustrative Synthesis of Intermediate Gen-10-r:
(3-Hydroxy-pyrrolidin-3-ylmethyl)-carbamic acid methyl ester
##STR00102##
[1077] Step i
[1078] To a solution of
3-Aminomethyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl
ester (120 mg, 0.56 mmol, 1 eq.) in MeCN (1 mL) are added TEA (156
.mu.L, 1.12 mmol, 2 eq.) followed by methyl chloroformate (42.7
.mu.L, 0.56 mmol, 1 eq.). The reaction mixture is stirred at r.t.
overnight, then is quenched with water and the aqueous layer is
extracted with EtOAc twice. The organic layer is washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The residue is purified by chromatography on silica gel (elution
DCM/MeOH: 100/01 to 94/6) to afford the expected product.
Step ii)
[1079] To a solution of the boc protected amine (94 mg, 0.34 mmol,
1 eq.) in dioxane (2 mL) is added an aqueous 12 M HCl solution
(12M) (144 .mu.L). The reaction mixture is stirred at r.t. for 4.5
days then concentrated in vacuo, to afford Intermediate
Gen-10-r.
1.2.12. General Method G4: General Synthesis of Intermediaire
Gen-11
##STR00103##
[1080] 1.2.12.1. General Method G4a
[1081] To a suspension of potassium carbonate (2.2 eq.) in water is
added the amine derivative (1 eq.). The reaction mixture is stirred
at r.t. until complete dissolution, then diluted with DCM and
cooled to 0.degree. C. prior to the dropwise introduction of
chloroacetyl chloride (1.2 eq.) over 30 min. After 2 h stirring at
r.t., the reaction mixture is filtered, the organic layer and the
aqueous phase are separated, and the aqueous phase is extracted
either with DCM or with a mixture of EtOAc/nBuOH 1:1. The combined
organic layers are dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue is suspended in acetone and
stirred vigorously for 20 min, filtered and the filtrate is
concentrated in vacuo to afford Intermediate Gen-11
1.2.12.2. Illustrative Synthesis of Intermediate Gen-11-a:
2-Chloro-1-(3-hydroxy-azetidin-1-yl)-ethanone
##STR00104##
[1083] To a suspension of potassium carbonate (13.9 g, 100 mmol,
2.2 eq.) in water (33.5 mL) is added hydroxyazetidine hydrochloride
(5 g, 45.6 mmol, 1 eq.). The reaction mixture is stirred at r.t.
until complete dissolution, then diluted with 33.5 mL of DCM and
cooled to 0.degree. C. prior to the dropwise introduction of
chloroacetyl chloride (4.4 mL, 54.8 mmol, 1.2 eq.) over 30 min.
After 2 h stirring at r.t., the reaction mixture is filtered, the
organic layer is separated, and the aqueous phase is extracted with
a mixture EtOAc/nBuOH (1/1) (6.times.16 mL). The combined organic
layers are dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. The residue is suspended in acetone (48 mL) and stirred
vigorously for 20 min, filtered and the filtrate is concentrated in
vacuo to afford Intermediate Gen-11-a.
[1084] .sup.1H NMR .delta. (ppm) (400 MHz, CDCl.sub.3): 4.77-4.68
(1 H, m), 4.50 (1 H, dd), 4.50 (1 H, dd), 4.32 (1 H, dd), 4.16 (1
H, dd), 3.89 (2 H, s), 2.55 (1 H, d).
1.2.12.3. General Method G4b
[1085] To a solution of chloroacetyl chloride (1 eq) and TEA (1.2
to 2 eq) in DCM at 0.degree. C. is added the amine derivative (1.1
to 1.2 eq.). The reaction mixture is stirred overnight at r.t.,
then concentrated in vacuo. The residue is suspended in acetone or
THF and stirred vigorously for 20 min filtered and the filtrate is
concentrated in vacuo to afford Intermediate Gen-11 which is used
directly without further purification in the next step.
1.2.12.4. Illustrative Synthesis of Intermediate Gen-11-f:
(R)-2-Chloro-1-(3-hydroxy-pyrrolidin-1-yl)-ethanone
##STR00105##
[1087] To a solution of chloroacetyl chloride (2 mL, 25.11 mmol, 1
eq) and TEA (4.19 mL, 30.13 mmol, 1.2 eq) in DCM (90 mL) at
0.degree. C. is added (R)-pyrrolidin-3-ol (2.41 g, 27.62 mmol, 1.1
eq.). The reaction mixture is stirred overnight at r.t., then
concentrated in vacuo. The residue is suspended in THF and stirred
vigorously for 20 min, filtered, washed with THF and the filtrate
is concentrated in vacuo to afford Intermediate Gen-11-f which is
used directly in the next step without further purification.
[1088] LC-MS: MW (calcd): 163 (.sup.35Cl), 165 (.sup.37Cl); m/z MW
(obsd): 164 (.sup.35Cl M+H), 166 (.sup.37Cl M+H)
1.2.12.5. General Method G4c
[1089] To a solution of chloroacetic acid (1 eq.) and the amine
derivative (1 eq.) in DCM are added TEA (1.5 to 3 eq.) and
Mukaiyama's resin (1.5 to 2 eq.). The reaction mixture is stirred
at r.t. overnight, then filtered. The resin is washed with DCM and
the filtrate is concentrated in vacuo. The residue is suspended in
acetone, filtered and the filtrate is concentrated in vacuo to
afford Intermediate Gen-11 which is used directly in the next step
without further purification.
1.2.12.6. Illustrative Synthesis of Intermediate Gen-11-l:
2-Chloro-1-(2-methyl-pyrrolidin-1-yl)-ethanone
##STR00106##
[1091] To a solution of chloroacetic acid (100 mg, 1.058 mmol, 1
eq.) and 2-methylpyrrolidine (102 mg, 1.058 mmol, 1 eq) in DCM (8
mL) are added TEA (441 .mu.L, 3.175 mmol, 3 eq.) and Mukaiyama's
resin (1.8 g, 2.12 mmol, 1.5 eq.). The reaction mixture is stirred
at r.t. overnight, then filtered. The resin is washed with DCM and
the filtrate is concentrated in vacuo. The residue is suspended in
acetone, filtered and the filtrate is concentrated in vacuo to
afford Intermediate Gen-11-l which used directly without further
purification in the next step.
EXAMPLE 2
Preparation of the Compounds of the Invention
2.1. Compound 52:
3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperazin-1-yl)propanamide
##STR00107##
##STR00108##
[1093] To Compound 51 (90 mg, 0.183 mmol, 1 eq.) is added
H.sub.2SO.sub.4 (2 mL), the reaction mixture is heated at
80.degree. C. for 1 h, then cooled to r.t. A saturated NaHCO.sub.3
solution, and potassium carbonate are added until a basic pH is
reached, then the reaction mixture is stirred at r.t. overnight.
The reaction mixture is diluted with DCM and the aqueous layer is
extracted three times with DCM. The combined organic layers are
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude product is purified by
chromatography on silica gel (elution with DCM/MeOH: 100 to 95/5)
to afford Compound 52.
[1094] LC-MS: MW (calcd): 508 m/z (obsd): 509 (M+H)
2.2. Compound 61:
(S)-7-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one
##STR00109##
##STR00110##
[1096] To a solution of compound 60 (40 mg, 0.086 mmol, 1 eq.) in
THF (1 mL) are added CDI (15 mg, 0.092 mmol, 1.1 eq.) and TEA
(0.018 g, 0.180 mmol, 2.1 eq.). The reaction mixture is stirred at
r.t. for 2 h, then concentrated in vacuo. The residue is partionned
between DCM and water. The aqueous layer is extracted three times
with DCM. The combined organic layers are washed with brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
crude product is purified by chromatography on silica gel (elution
with DCM/MeOH: 98/2) to afford Compound 61.
[1097] LC-MS: MW (calcd): 493 m/z (obsd): 494 (M+1)
2.3. Compound 62:
(S)--N-(2-ethyl-6-(3-(methoxymethyl)-4-(methylsulfonyl)piperazin-1-yl)imi-
dazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine
##STR00111##
[1098] Step i)
##STR00112##
[1100] To a solution of Compound 59 (60 mg, 0.11 mmol, 1 eq.) in
DMF (1 mL) at 0.degree. C. is added NaH (60% in oil suspension, 6
mg, 0.16 mmol, 1.5 eq.), the reaction mixture is strirred at
0.degree. C. for 45 min, then methyl iodide (14 .mu.L, 0.22 mmol, 2
eq.) is added and stirred at r.t. for 2 h. Then quenched with water
and diluted with EtOAc, the aqueous layer is extracted with EtOAc
twice. The combined organic layers are washed with brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford
Intermediate Gen-5-ac.
[1101] LC-MS: MW (calcd): 581 m/z (obsd): 582 (M+H)
Step ii)
##STR00113##
[1103] Boc deprotection of intermediate
(S)-4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidaz-
o[1,2-b]pyridazin-6-yl)-2-methoxymethyl-piperazine-1-carboxylic
acid tert-butyl ester (Gen-5-ac) is performed according to general
method E5b to afford Intermediate Gen-5-ad.
[1104] LC-MS: MW (calcd): 481 m/z (obsd): 482 (M+H)
Step iii)
##STR00114##
[1105] Intermediate
[2-Ethyl-6-((S)-3-methoxymethyl-piperazin-1-yl)-imidazo[1,2-b]pyridazin-3-
-yl]-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine (Gen-5-ad) is
sulfonylated with methanesulfonyl chloride using general method E11
to give Compound 62.
[1106] LC-MS: MW (calcd): 559 m/z (obsd): 560 (M+H)
2.4. Compound 66:
(S)-8-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(1H)-one
##STR00115##
[1107] Step i)
##STR00116##
[1109] Intermediate Gen-5-ae is coupled with chloroacetyl chloride
using general method E9b to give
1-[2-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2-ethyl-3-{[4-(4-fluoro-ph-
enyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-b]pyridazin-6-yl)-piperazin--
1-yl]-2-chloro-ethanone.
Step ii)
##STR00117##
[1111] Silyl deprotection of
1-[2-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2-ethyl-3-{[4-(4-fluoro-ph-
enyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-b]pyridazin-6-yl)-piperazin--
1-yl]-2-chloro-ethanone is performed according to general method
E19 to afford
2-Chloro-1-[4-(2-ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methy-
l-amino}-imidazo[1,2-b]pyridazin-6-yl)-2-hydroxymethyl-piperazin-1-yl]-eth-
anone.
Step iii)
##STR00118##
[1112]
2-Chloro-1-[4-(2-ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-
-amino}-imidazo[1,2-b]pyridazin-6-yl)-2-hydroxymethyl-piperazin-1-yl]-etha-
none (27 mg, 0.050 mmol, 1 eq.) is dissolved in THF (1 mL). After
cooling to 0.degree. C., potassium tert-butoxide (7 mg, 0.06 mmol,
1.2 eq.) is added. The reaction mixture is stirred 15 min at
0.degree. C. and 1 h at r.t., then quenched with one drop of acetic
acid and diluted with a saturated Na.sub.2CO.sub.3 solution. The
aqueous layer is extracted three times with EtOAc. The combined
organic layers are washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. Compound 66 is obtained by
chromatography on silica gel (elution with DCM/MeOH: 100/0 to
95/5).
[1113] LC-MS: MW (calcd): 507 m/z (obsd): 508 (M+H)
2.5. Compound 89:
N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,-
2-b]pyridazin-6-yl)piperidin-4-yl)pyrrolidine-1-carboxamide
##STR00119##
[1114] Step i)
##STR00120##
[1116] To a solution of Compound 82 (100 mg, 0.20 mmol, 1 eq.) in
THF (0.5 mL) are successively added TEA (83 .mu.L, 0.60 mmol, 3
eq.) and 1,1'-Carbonyldiimidazole (0.133 g, 0.82 mmol, 4 eq.). The
reaction mixture is heated at 50.degree. C. for 6 h and stirred at
r.t. overnight. Water is added to the solution and the aqueous
layer is extracted with EtOAc three times. The combined organic
layers are washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford Intermediate
Gen-5-l.
[1117] LC-MS: MW (calcd): 545 m/z (obsd): 546 (M+H)
Step ii)
##STR00121##
[1119] To a solution of Gen-5-l (80 mg, 0.15 mmol, 1 eq.) in DMF (1
mL) is added pyrrolidine (25 .mu.L, 0.30 mmol, 2 eq.). The reaction
mixture is stirred at r.t. for 3 h and quenched with a saturated
NaHCO.sub.3 solution. The aqueous layer is extracted with EtOAc
three times. The organic layer is washed with water and brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The crude product is purified by chromatography on silica gel
(elution with DCM/MeOH: 100/0 to 97/3) to afford Compound 89.
[1120] LC-MS: MW (calcd): 548 m/z (obsd): 549 (M+H)
2.6. Compound 130:
1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-6-yl)pyrrolidin-3-yl formate
##STR00122##
[1121] Step i)
##STR00123##
[1123] To a solution of Compound 129 (400 mg, 0.912 mmol, 1 eq.) in
DCM (20 mL) are added TEA (380 .mu.L, 2.736 mmol, 3 eq.) and
sulfonyl chloride (141 .mu.L, 1.824 mmol, 2 eq.). The reaction
mixture is stirred at r.t. for 1.5 h, then quenched with water. The
aqueous layer is extracted with EtOAc and the organic layer is
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to afford Gen-5-ab.
[1124] LC-MS: MW (calcd): 516 m/z (obsd): 517 (M+H)
Step ii)
##STR00124##
[1126] To a solution of Intermediate Gen-5-ab (50 mg, 0.097 mmol, 1
eq.) in DMF (4 mL) is added thiomorpholine (28 .mu.L, 0.290 mmol, 3
eq.). The reaction mixture is irradiated at 200.degree. C. for 15
min, then partionned between EtOAc and water. The aqueous layer is
extracted with EtOAc and the organic layer is washed with water and
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude product is purified by column chromatography
(elution with DCM/MeOH: 100/98 to 95/5) to afford Compound 130.
[1127] LC-MS: MW (calcd): 466 m/z (obsd): 467 (M+H)
2.7. Compound 132:
1-(3-((5-chloro-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimid-
azo[1,2-b]pyridazin-6-yl)pyrrolidin-3-one
##STR00125##
##STR00126##
[1129] In a flask under nitrogen flow are introduced a solution of
oxalyl chloride (91 .mu.L, 0.953 mmol, 2.2 eq.) in DCM (7 mL), and
DMSO (123 .mu.L), the reaction mixture is cooled to -78.degree. C.
A solution of compound 129 (190 mg, 0.433 mmol, 1 eq.) in DCM (3
mL) is slowly introduced to the reaction mixture. The reaction
mixture is stirred at -78.degree. C. for 1.25 h, then TEA (361
.mu.L, 2.6 mmol, 6 eq.) is added and the solution is stirred for a
further 1 h. After warming-up to r.t., the reaction mixture is
partionned between water and DCM. The aqueous layer is extracted
with DCM, the organic layer is washed with water and brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give
Compound 132.
[1130] LC-MS: MW (calcd): 470 (.sup.35Cl), 472 (.sup.37Cl); m/z MW
(obsd): 471 (.sup.35Cl M+H), 473 (.sup.37Cl M+H)
2.8. Compound 138:
(S)-1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1-
,2-b]pyridazin-6-yl)pyrrolidine-2-carboxylic acid
##STR00127##
##STR00128##
[1132] To a solution of Intermediate Gen-4-a (100 mg, 0.231 mmol, 1
eq.), L-proline (11 mg, 0.092 mmol, 0.4 eq.), CuI (9 mg, 0.046
mmol, 0.2 eq.) and cesium carbonate (301 mg, 0.925 mmol, 4 eq.) in
dry DMSO under argon is added 4-Ethoxy-3-oxo-butyric acid ethyl
ester (43 .mu.L, 0.277 mmol, 1.2 eq.). The reaction mixture is
heated at 50.degree. C. overnight and at r.t. for 4 days. The
solution is quenched by a saturated NH.sub.4Cl solution, diluted
with EtOAc and filtered. The solid is washed with EtOAc and dried
in vacuo to afford Compound 138.
[1133] LC-MS: MW (calcd): 466 m/z (obsd): 467 (M+H)
2.9. Compound 195:
(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)--
1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)methanol
##STR00129##
[1134] Step i)
##STR00130##
[1136] To a solution of Intermediate Gen-4-i (2.03 g, 4 mmol, 1
eq.) in DCM (150 mL) cooled at 3.degree. C. are added osmium
tetraoxide (in t-BuOH, 2.03 g, 0.2 mmol, 0.05 eq.),
N-methylmorpholine-4-oxide (811 mg, 6 mmol, 1.5 eq.) and the
reaction kept stirring. After 30 min an additional portion of
N-methylmorpholine-4-oxide (541 mg, 4 mmol, 1 eq.) is added, this
operation is performed seven times but with 0.5 eq. of
N-methylmorpholine-4-oxide (until complete conversion of starting
material is observed). The reaction is quenched by addition of
water (500 mL). The two layers are separated and the aqueous layer
is extracted with DCM (200 mL) twice. The combined organic layers
are dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude product is purified by chromatography on silica
gel (elution with DCM/MeOH: 100/0 to 97/3) to give Intermediate
Gen-4-j.
[1137] LC-MS: MW (calcd): 539 (.sup.79Br), 541 (.sup.81Br); m/z
(obsd): 540 (.sup.79Br M+H), 542 (.sup.81Br M+H)
Step ii)
##STR00131##
[1139] A solution of
1-(6-bromo-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b-
]pyridazin-2-yl)-2-phenylethane-1,2-diol (Gen-4-j) (4.70 g, 8.70
mmol, 1 eq.) in DCM (300 mL) is cooled to -4.degree. C. Lead
tetraacetate (dried before use, 5.79 g, 13.05 mmol, 1.5 eq.) is
added and stirred at -11.degree. C. for 20 min. The reaction is
quenched by addition of water (500 mL) and brine (300 mL). The
mixture is filtered and the two layers of the biphasic filtrate are
separated. The aqueous layer is extracted with DCM (400 mL) twice.
The combined organic layers are dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The crude product is purified
by chromatography on silica gel (elution with heptane/EtOAc: 100/0
to 50/50) to give Intermediate Gen-4-k.
[1140] LC-MS: MW (calcd): 431 (.sup.79Br), 433 (.sup.81Br); m/z
(obsd): 432 (.sup.79Br M+H), 434 (.sup.81Br M+H).
Step iii)
##STR00132##
[1141] Suzuki coupling of Intermediate Gen-4-k with
1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,-
6-tetrahydropyridine according to general method E2 affords
Intermediate Gen-5-aag.
[1142] LC-MS: MW (calcd): 512; MW (obsd): 513 (M+H)
Step iv)
##STR00133##
[1144] To a solution of intermediate
3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsylfonyl)-1-
,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazine-2-carbaldehyde
(Gen-5-aag) (50 mg, 0.098 mmol, 1 eq.) in DCM/MeOH (1 mL/1 mL)
under nitrogen atmosphere at r.t. is added sodium borohydride (7.4
mg, 0.195 mmol, 2 eq.). The reaction is stirred at r.t. for 1 h,
then quenched with excess of water, filtered off and concentrated
in vacuo. The crude product is purified by chromatography on silica
gel (elution with DCM/MeOH: 99/1 to 97/3) to afford Compound
195.
[1145] LC-MS: MW (calcd): 514; MW (obsd): 515 (M+H)
2.10. Compound 196:
2-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl-
)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetonitrile
##STR00134##
[1146] Step i)
##STR00135##
[1148] To a solution of Compound 195 (643 mg, 1.25 mmol, 1 eq.) in
DCM (50 mL) is added thionyl chloride (297 mg, 2.5 mmol, 2 eq.),
the reaction mixture is stirred at r.t. for 1 h. The mixture is
diluted with a saturated NaHCO.sub.3 solution (50 mL), then
extracted with DCM (10 mL) three times. The combined, organic
layers are dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. The crude is purified by chromatography on silica gel
(elution with DCM/MeOH: 100/0 to 97/3) to give Intermediate
Gen-5-z.
[1149] LC-MS: MW (calcd): 532 (.sup.35Cl), 534 (.sup.37Cl); m/z
(obsd): 533 (.sup.35Cl M+H), 535 (.sup.37Cl M+H).
Step ii)
##STR00136##
[1151]
[2-Chloromethyl-6-(1-methanesulfonyl-piperidin-4-yl)-imidazo[1,2-b]-
pyridazin-3-yl]-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine
(Gen-5-z) (560 mg, 1.05 mmol, 1 eq.) and potassium cyanide (103 mg,
1.575 mmol, 1.5 eq.) are dissolved in dry DMSO (6 mL). The reaction
mixture is heated at 50.degree. C. for 3.5 h, after cooling to r.t.
the mixture is quenched by addition of a saturated NaHCO.sub.3
solution (100 mL) and extracted with DCM (20 mL) three times. The
combined organic layers are washed with water, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude is
purified by chromatography on silica gel (elution with DCM/MeOH:
100/0 to 97.5/2.5) to afford Compound 196.
[1152] LC-MS: MW (calcd): 523; MW (obsd): 524 (M+H)
2.11. Compound 197:
3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl-
)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propanamide
##STR00137##
[1153] Step i
##STR00138##
[1155] Trimethyl phosphonacetate (206 .mu.L, 1.272 mmol, 1.1 eq.)
is dissolved in dry THF (20 mL). Sodium hydride is added (60% in
oil suspension, 53 mg, 1.330 mmol, 1.15 eq.). The mixture is
stirred at r.t. for 10 min, then cooled to -78.degree. C. A
solution of
6-bromo-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-b]py-
ridazine-2-carbaldehyde (Gen-4-k), described in Compound 195, (500
mg, 1.157 mmol, 1 eq.) in dry THF (20 mL) is added dropwise. The
mixture is stirred for 1 h at -78.degree. C., allowed to warm to
r.t. and stirred for 1 h. The mixture is diluted with water and
DCM, the aqueous layer is extracted with DCM twice. The combined
organic layers are washed twice with a saturated NaHCO.sub.3
solution, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The product is purified by column chromatography (elution
with heptane./EtOAc: 90/10 to 0/100) to give Intermediate
Gen-4-l.
[1156] LC-MS: MW (calcd): 487 (.sup.79Br), 489 (.sup.81Br); m/z
(obsd): 488 (.sup.79Br M+H), 490 (.sup.81Br M+H).
Step ii)
##STR00139##
[1158] Suzuki coupling of
(E)-methyl-3-(6-bromo-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)im-
idazo[1,2-b]pyridazin-2-yl)acrylate (Gen-4-l) with
1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,-
6-tetrahydropyridine following general method E2 affords
Intermediate Gen-5-aah.
[1159] LC-MS: MW (calcd): 568; MW (obsd): 569 (M+H).
Step iii)
##STR00140##
[1160] Reduction of Intermediate Gen-5-aah is performed according
general method E6 to give Intermediate Gen-5-aai.
[1161] LC-MS: MW (calcd): 572; m/z (obsd): 573 (M+H).
Step iv)
##STR00141##
[1163] To a solution of
methyl-3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-methylsu-
fonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propanoate.
(Gen-5-aai) (256 mg, 0.447 mmol, 1 eq.) in THF (4 mL) are added
MeOH (4 mL) and a 2 M NaOH solution (4 mL, 8.00 mmol, 17.9 eq.).
The mixture is stirred at r.t. for 2 h. Organic solvent are
evaporated in vacuo. The aqueous layer is acidified with a 1 M HCl
solution to slightly acid. The aqueous layer is extracted with DCM
four times, the combined organic layers are dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford
Gen-5-aaj.
[1164] LC-MS: MW (calcd): 558; m/z (obsd): 559 (M+H).
Step iv)
##STR00142##
[1166] A solution of
3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-methylsulfonyl)-
piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propanoic acid
(Gen-5-aaj) (50 mg, 0.090 mmol, 1 eq.) and TEA (50 .mu.L, 0.358
mmol, 4 eq.) in dry DMF (2 mL). is stirred for 10 min. Ammonium
chloride (9.58 mg, 0.179 mmol, 2 eq.) followed by propane
phosphonic acid anhydride (114 mg, 0.179 mmol, 1.5 eq.) are added,
and the resulting mixture is stirred at r.t. overnight. The
reaction mixture is quenched with water and diluted with EtOAc, the
aqueous layer is extracted with EtOAc. The combined organic layers
are washed twice with a saturated NaHCO.sub.3 solution and brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
afford the expected Compound 197.
[1167] LC-MS: MW (calcd): 557; m/z (obsd): 558 (M+H).
2.12. Compound 198:
3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl-
)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propanenitrile
##STR00143##
##STR00144##
[1169] A diluted solution of Compound 197 (100 mg, 0.179 mmol, 1
eq.) in pyridine dried on molecular sieves (powder 4 angstrom) (15
mL) is stirred at -5.degree. C. under nitrogen and treated dropwise
with trifluoroacetic acid anhydride (250 .mu.L, 1.79 mmol, 10 eq.)
in 10 additions of 25 .mu.L every 30 min. Solvent are evaporated in
vacuo. The residue is diluted with water and DCM. The aqueous layer
is extracted with DCM twice, the combined organic layers are washed
three times with water and brine, is dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to obtain Compound 198.
[1170] LC-MS: MW (calcd): 539; m/z (obsd): 540 (M+H).
2.13. Compound 199:
3-(3-((4-(4-fluorophenyl)-5-(2,2,2-trifluoroacetoyl)thiazol-2-yl)(methyl)-
amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)pr-
opanenitrile
##STR00145##
##STR00146##
[1172] To a solution of Compound 197 (483 mg, 0.087 mmol, 1 eq.) in
pyridine (2 mL) at 0.degree. C., is added dropwise trifluoroacetic
anhydride (73 .mu.L, 0.520 mmol, 6 eq.). The reaction mixture is
stirred at 0.degree. C. for 1 h, then allowed to warm up to r.t.
for 1 h, then concentrated in vacuo. The residue is partionned
between water and DCM, the aqueous layer is extracted with DCM
twice, the combined organic layers are washed with water three
times and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude is purified by chromatography on
silica gel (DCM/MeOH: 99/1 to 90/10) to afford the expected
Compound 199.
[1173] LC-MS: MW (calcd): 635; m/z (obsd): 636 (M+H).
2.14. Compound 200:
3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl-
)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propan-1-ol
##STR00147##
##STR00148##
[1175] To a solution of intermediate
3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-methylsulfonyl)-
piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propanoic acid.
(Gen-5-aaj) (50 mg, 0.090 mmol, 1 eq.) in dry THF (6 mL) are added
TEA (15 .mu.L, 0.107 mmol, 1.2 eq.) followed by isobutyl
chloroformate (14 .mu.L, 0.107 mmol, 1.2 eq.). The reaction mixture
is stirred at r.t. for 1 h, then sodium borohydride (14 mg, 0.358
mmol, 4 eq.) is added followed by addition of absolute ethanol (1
mL). The reaction mixture is stirred at r.t. for 2 h, then quenched
with a 1 M HCl solution, diluted with water and DCM. The aqueous
layer is extracted with DCM twice, the combined organic layers are
washed with water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The crude is purified by preparative
LC-MS to afford the expected Compound 200.
[1176] LC-MS: MW (calcd): 544; m/z (obsd): 545 (M+H)
2.15. Compound 219:
2-(5-((2-ethyl-6-(piperidin-4-yl)imidazo[1,2-b]pyridazin-3-yl)(methyl)ami-
no)-1,2,4-thiadiazol-3-yl)-5-fluorobenzonitrile
##STR00149##
[1177] Step i)
##STR00150##
[1179] To a solution of intermediate
4-(2-Ethyl-3-methylamino-imidazo[1,2-b]pyridazin-6-yl)-piperidine-1-carbo-
xylic acid tert-butyl ester (Gen-7-a) (1 g, 2.78 mmol, 1 eq.) in
MeCN (5 mL) under argon are added
3-Bromo-5-chloro-[1,2,4]thiadiazole (1.66 g, 8.35 mmol, 3 eq.)
followed by DIPEA (484 .mu.L, 2.78 mmol, 1 eq.). The reaction
mixture is heated at 90.degree. C. for 20 h, then concentrated in
vacuo. The crude is purified by chromatography on silica gel
(DCM/MeOH: 100/0 to 98/2) to afford Intermediate Gen-5-an.
[1180] LC-MS: MW (calcd): 521 (.sup.79Br), 523 (.sup.81Br); m/z
(obsd): 522 (.sup.79Br M+H), 524 (.sup.81Br M+H).
Step ii)
##STR00151##
[1182] To a solution of intermediate
4-{3-[(3-Bromo-[1,2,4]thiadiazol-5-yl)-methyl-amino]-2-ethyl-imidazo[1,2--
b]pyridazin-6-yl}-piperidine-1-carboxylic acid tert-butyl ester
(Gen-5-an) (261.2 mg, 0.5 mmol, 1 eq.) in a mixture of dioxane (1.5
mL) and water (150 .mu.L) under argon are successively added CsF
(159.5 mg, 1.05 mmol, 2.1 eq.),
5-Fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo-
nitrile (148.2 mg, 0.6 mmol, 1.2 eq.), and then Pd(amphos)Cl.sub.2
(35.4 mg, 0.049 mmol, 0.1 eq.). The reaction mixture is heated at
80.degree. C. for 4 days. After cooling to r.t., the crude product
is partionned between water and EtOAc and the layers are separated.
The aqueous layer is extracted with a mixture of EtOAc and
Et.sub.2O twice, the combined organic layers are dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The residue is purified
by chromatography on silica gel (DCM/MeOH: 100/0 to 92/8) to afford
Intermediate Gen-5-ao
[1183] LC-MS: MW (calcd): 562; m/z MW (obsd): 563 (M+H)
Step iii)
##STR00152##
[1184] Boc deprotection of intermediate
4-(3-{[3-(2-Cyano-4-fluoro-phenyl)-[1,2,4]thiadiazol-5-yl]-methyl-amino}--
2-ethyl-imidazo[1,2-b]pyridazin-6-yl)-piperidine-1-carboxylic acid
tert-butyl ester (Gen-5-ao) is performed according to general
method E5b to afford Compound 219.
[1185] LC-MS: MW (calcd): 462 m/z (obsd): 463 (M+H)
2.16. Intermediate Gen-9-e:
2-Chloro-4-(4-fluoro-phenyl)-pyrimidine-5-carbonitrile
##STR00153##
##STR00154##
[1186] Step i)
[1187] To 3-(4-Fluoro-phenyl)-3-oxo-propionitrile (3 g, 18.3 mmol,
1 eq.) is added N,N-Dimethylformamide dimethyl acetal (7.32 mL,
55.163 mmol, 3 eq.). The reaction mixture is stirred at r.t. for 15
min. The reaction mixture is diluted with water, and the solid is
filtered off, washed with water and dried in vacuo. The crude is
purified by cake of silica gel (elution with DCM/MeOH: 100/3) to
afford the expected product.
[1188] LC-MS: MW (calcd): 218; m/z MW (obsd): 219 (M+H)
Step ii)
[1189] To a solution of
3-Dimethylamino-2-(4-fluoro-benzoyl)-acrylonitrile (1.78 g, 8.15
mmol, 1 eq.) in EtOH (44.5 mL) at r.t. are added guanidine
carbonate salt (5.87 g, 32.6 mmol, 4 eq.) and sodium acetate (6.02
g, 73.4 mmol, 9 eq.). The reaction mixture is refluxed for 3 h,
then cooled to r.t., and diluted with DCM (45 mL). The crude
product is filtered on Celpure.RTM. P65, washed with a mixture of
DCM/EtOH (15 mL/15 mL) three times and the filtrate is concentrated
in vacuo to afford the expected product.
[1190] LC-MS: MW (calcd): 214; m/z MW (obsd): 215 (M+H)
Step iii)
[1191] To a solution of
2-Amino-4-(4-fluoro-phenyl)-pyrimidine-5-carbonitrile (600 mg, 8.80
mmol, 1 eq.) and copper(II) chloride (451.9 mg, 3.36 mmol, 1.2 eq.)
in dry MeCN (24 mL) under argon is added dropwise tert-butyl
nitrite (0.5 mL, 4.20 mmol, 1.5 eq.). The reaction mixture is
refluxed for 2 h, after cooling to r.t. the reaction mixture is
diluted with Et.sub.2O. The organic layer is washed with water
three times, dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. The crude is purified by chromatography on silica gel
(elution heptane/EtOAc: 100/0 to 80/20) to afford the expected
Intermediate Gen-9-e.
[1192] LC-MS: MW (calcd): 233 (.sup.35Cl), 235 (.sup.37Cl); m/z MW
(obsd): 234 (.sup.35Cl M+H), 236 (.sup.37Cl M+H)
2.17. Intermediate Gen-10-a: Piperidine-4-sulfonic acid
cyclopropylamide
##STR00155##
##STR00156##
[1193] Step i)
[1194] To a solution of cyclopropylamine (39 .mu.L, 0.566 mmol, 1.2
eq.) in DCM (2 mL) are added TEA (197 .mu.L, 1.416 mmol, 3 eq.) and
4-Chlorosulfonyl-piperidine-1-carboxylic acid benzyl ester (150 mg,
0.472 mmol, 1 eq.). The reaction mixture is stirred at r.t. for 24
h. The crude product is quenched with water and diluted with DCM,
the aqueous layer is extracted with DCM. The combined organic
layers are washed with a saturated NaHCO.sub.3 solution and brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The residue is purified by chromatography on silica gel (elution
DCM/MeOH: 100/0 to 95/5) to afford the expected product.
Step ii)
[1195] To a solution of
4-Cyclopropylsulfamoyl-piperidine-1-carboxylic acid benzyl ester
(115 mg, 0.340 mmol, 1 eq.) in MeOH (2 mL) is added Pd/C (12 mg,
10%). The flask is evacuated and backfilled with argon. Then the
reaction is evacuated and backfilled with H.sub.2 and stirred at
r.t. overnight. The crude product is filtered through a pad of
Clarcel and washed with MeOH. The filtrate is concentrated in vacuo
to afford Intermediate Gen-10-a.
2.18. Intermediate Gen-10-j:
1-(2-Piperazin-1-yl-ethyl)-pyrrolidin-2-one
##STR00157##
##STR00158##
[1196] Step i)
[1197] To a solution of 1-(2-Hydroxy-ethyl)-pyrrolidin-2-one (300
.mu.L, 2.657 mmol, 1 eq.) in DCM (4 mL) is added
1-Chloro-N,N,2-trimethyl-1-propenylamine (527 .mu.L, 3.986 mmol,
1.5 eq.). The reaction mixture is stirred at r.t. for 1 h. The
crude product is quenched with water and diluted with DCM, the
aqueous layer is extracted with DCM. The combined organic layers
are washed with water and brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo, to afford
1-(2-Chloro-ethyl)-pyrrolidin-2-one.
Step ii)
[1198] To a solution of Boc-piperazine (200 mg, 1.074 mmol, 1 eq.)
in MeCN (5 mL) are added TEA (299 .mu.L, 2.148 mmol, 2 eq.) and
1-(2-Chloro-ethyl)-pyrrolidin-2-one (238 mg, 1.611 mmol, 1.5 eq.).
The reaction mixture is heated at 190.degree. C. under microwave
irradiation for 1.2 h. After cooling, the reaction mixture is
concentrated in vacuo, then the crude product is partionned between
water and DCM, the aqueous layer is extracted with DCM three times.
The combined organic layers are washed with water and brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue is purified by chromatography on silica gel (elution
DCM/MeOH: 100 to 95/5) to afford the expected intermediate.
Step iii)
[1199] To a solution of the above boc protected amine (149 mg,
0.501 mmol, 1 eq.) in MeOH (2 mL) is added a 4 M HCl solution in
dioxane (3 mL). The reaction mixture is stirred at r.t. overnight
then concentrated in vacuo, to afford the expected intermediate
Gen-10-j as hydrochloride salt which used directly in the next step
without purification.
2.19. Intermediate Gen-10-l:
N,N-Dimethyl-2-piperazin-1-yl-acetamide
##STR00159##
##STR00160##
[1200] Step i)
[1201] To a solution of N-boc piperazine (150 mg, 0.81 mmol, 1 eq.)
in MeCN (2 mL) are added TEA (224 .mu.L, 1.61 mmol, 2 eq.) and
2-Chloro-N,N-dimethyl-acetamide (124 .mu.L, 1.21 mmol, 1.5 eq.).
The reaction mixture is stirred at r.t. for 4 h. The crude product
is quenched with water and diluted with DCM, the aqueous layer is
extracted with DCM. The combined organic layers are washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to afford the expected product.
Step ii)
[1202] To a solution of the above boc protected amine (216 mg, 0.8
mmol, 1 eq.) in a mixture of MeOH (3 mL) and dioxane (3 mL) is
added a 4 M HCl solution in dioxane (995 .mu.L). The reaction
mixture is stirred at r.t. for 2.5 days then concentrated in vacuo.
The crude is triturated in Et.sub.2O, filtered off and dried to
afford the expected Intermediate Gen-10-l as hydrochloride salt
which used directly in the next step without purification.
2.20. Intermediate Gen-10-o:
1-Oxa-3,7-diaza-spiro[4.4]nonan-2-one
##STR00161##
##STR00162##
[1203] Step i)
[1204] To a solution of
3-Aminomethyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl
ester (200 mg, 0.93 mmol, 1 eq.) in MeCN (2 mL) are added TEA (130
.mu.L, 0.93 mmol, 1 eq.) and 4-nitrophenyl chloroformate (186 mg,
0.93 mmol, 1 eq.). The reaction mixture is stirred at r.t. for 2.5
days, then heated at 75.degree. C. overnight, and the crude product
is concentrated in vacuo. The residue is purified by chromatography
on silica gel (elution DCM/MeOH: 100/0 to 95/5) to afford the
expected product.
Step ii)
[1205] To a solution of the boc protected amine (110 mg, 0.45 mmol,
1 eq.) in dioxane (2 mL) is added an aqueous 12 M HCl solution (152
.mu.L). The reaction mixture is stirred at r.t. overnight then
concentrated in vacuo, to afford Intermediate Gen-10-o.
2.21. Intermediate Gen-10-x: 4-Morpholin-4-yl-pyrrolidin-3-ol
##STR00163##
##STR00164##
[1206] Step i)
[1207] To a solution of 2,5-dihydro-pyrrole-1-carboxylic acid
tert-butyl ester (100 mg, 0.591 mmol, 1 eq.) in DCM (1.4 mL) is
added m-CPBA (335.1 mg, 1.359 mmol, 2.3 eq.), the reaction mixture
is stirred at r.t. overnight. The crude product is quenched with a
1 M NaOH solution and diluted with DCM, the aqueous layer is
extracted with DCM twice. The combined organic layers are dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo, the
residue is purified by chromatography on silica gel (elution
heptane/EtOAc: 100/0 to 60/40) to afford the expected product.
[1208] LC-MS: MW (calcd): 185; m/z MW (obsd): 186 (M+H)
Step ii)
[1209] To a solution of
6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester
(70 mg, 0.378 mmol, 1 eq.) in EtOH (0.4 mL) is added morpholine
(36.6 .mu.L, 0.416 mmol, 1.1 eq.). The reaction mixture is heated
at 130.degree. C. under microwave irradiation for 40 min, then
morpholine (36.6 .mu.L, 0.416 mmol, 1.1 eq.) is added and the
reaction mixture is another heated at 130.degree. C. under
microwave irradiation for 40 min. The reaction mixture is
concentrated in vacuo, the residue is purified by chromatography on
silica gel (elution DCM/MeOH: 100/0 to 90/10) to afford the
expected product.
[1210] LC-MS: MW (calcd): 272; m/z MW (obsd): 273 (M+H)
Step iii)
[1211] To a solution of the above boc protected amine (95 mg, 0.349
mmol, 1 eq.) in dioxane (0.75 mL) is added a 4 M HCl solution in
dioxane (0.70 mL). The reaction mixture is stirred at r.t. for 6 h
then concentrated in vacuo, to afford the expected Intermediate
Gen-10-x as hydrochloride salt which used directly in the next step
without purification.
[1212] LC-MS: MW (calcd): 172; m/z MW (obsd): 173 (M+H)
2.22. Intermediate Gen-10-aa:
4-Methoxy-1-pyrrolidin-3-yl-piperidine
##STR00165##
##STR00166##
[1213] Step i)
[1214] To a solution of 4-hydroxypiperidine (901.1 mg, 8.909 mmol,
3.3 eq.) in DCE (20 mL) is added N-boc-3-pyrrolidinone (500 mg,
2.699 mmol, 1 eq.). The reaction mixture is stirred at r.t. then
NaBH(OAc).sub.3 (2.86 g, 13.497 mmol, 5 eq.) is added. The reaction
mixture is stirred at r.t. overnight, then concentrated in vacuo.
The residue is dissolved in a mixture of DCM and a saturated
NaHCO.sub.3 solution, the two phases are separated and the aqueous
phase is extracted with DCM twice. The combined organic layers are
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue is purified by chromatography on
silica gel (elution DCM/MeOH: 100/0 to 90/10) to afford the
expected product.
[1215] LC-MS: MW (calcd): 270; m/z MW (obsd): 271 (M+H)
Step ii)
[1216] To a solution of
3-(4-Hydroxy-piperidin-1-yl)-pyrrolidine-1-carboxylic acid
tert-butyl ester (300 mg, 1.109 mmol, 1 eq.) in dry DMF (3 mL) are
added NaH (60% in oil suspension, 66.6 mg, 1.664 mmol, 1.5 eq.) and
methyl iodide (82.2 .mu.L, 1.332 mmol, 1.2 eq.). The reaction
mixture is stirred at r.t. overnight, then the reaction mixture is
quenched with water, and diluted with AcOEt, the layers are
separated, the aqueous layer is extracted with AcOEt. The combined
organic layers are dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. The expected product is obtained by chromatography on silica
gel (elution DCM/MeOH: 100/0 to 90/10).
[1217] LC-MS: MW (calcd): 284; m/z MW (obsd): 285 (M+H)
Step iii)
[1218] To a solution of the above boc protected amine (150 mg,
0.527 mmol, 1 eq.) in dioxane (1.1 mL) is added a 4 M HCl solution
in dioxane (1.1 mL). The reaction mixture is stirred at r.t. for 7
h then concentrated in vacuo, to afford the expected intermediate
Gen-10-aa as hydrochloride salt which used directly in the next
step the next step without purification.
2.23. Intermediate Gen-10-ab:
2-(1-Methanesulfonyl-piperazin-2-yl)-ethanol
##STR00167##
##STR00168##
[1219] Step i)
[1220] To a solution of
3-Methoxycarbonylmethyl-piperazine-1-carboxylic acid tert-butyl
ester (700 mg, 2.71 mmol, 1 eq.) in DCM (9 mL) are added TEA (1.13
mL, 8.13 mmol, 3 eq.) and mesyl chloride (231 .mu.L, 2.98 mmol, 1.1
eq.). The reaction mixture is stirred at r.t. overnight. The crude
product is quenched with water and a saturated NaHCO.sub.3 solution
and diluted with DCM, the aqueous layer is extracted with DCM three
times. The combined organic layers are washed with brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue is purified by chromatography on silica gel (elution with
heptane/EtOAc: 70/30 to 50/50) to afford the expected product.
Step ii)
[1221] To a solution of
4-Methanesulfonyl-3-methoxycarbonylmethyl-piperazine-1-carboxylic
acid tert-butyl ester (150 mg, 0.45 mmol, 1 eq.) in dry THF (2 mL)
at 0.degree. C. is added dropwise a 1 M LiAlH.sub.4 solution in THF
(670 .mu.L, 0.67 mmol, 1.5 eq.). The reaction mixture is stirred at
0.degree. C. then at r.t. overnight. The crude product is filtered
through a pad of Clarcel, washed with THF and DCM, and the filtrate
is concentrated in vacuo. The crude is purified by chromatography
on silica gel (elution DCM/MeOH: 98/2 to 96/4) to afford the
expected product.
Step iii)
[1222] To a solution of the above boc protected amine (95 mg, 0.31
mmol, 1 eq.) in dioxane (2 mL) is added a 4 M HCl solution in
dioxane (385 .mu.L). The reaction mixture is stirred at r.t.
overnight, then a 4 M HCl solution in dioxane (800 .mu.L) is added
again, and stirred at r.t. overnight, then concentrated in vacuo to
afford the expected Intermediate Gen-10-ab as hydrochloride salt
which used directly in the next step without purification.
2.24. Intermediate Gen-10-ac:
1-(4-Methoxy-benzyl)-3-piperazin-1-yl-pyrrolidin-2-one
##STR00169##
##STR00170##
[1223] Step i)
[1224] To a solution of Boc-piperazine (204.5 mg, 1.1 mmol, 1.1
eq.) in dry DMF (8.3 mL) are added potassium carbonate (276.4 mg,
2.0 mmol, 2 eq.), 3-Bromo-1-(4-methoxy-benzyl)-pyrrolidin-2-one
(284.2 mg, 1. mmol, 1 eq.) and NaI (149.9 mg, 1 mmol, 1 eq.). The
reaction mixture is stirred at r.t. overnight, then Boc-piperazine
(37.3 mg, 0.2 mmol, 0.2 eq.) and the reaction mixture is stirred at
r.t. for 2 h. The reaction mixture is quenched with water and
diluted with EtOAc, the aqueous layer is extracted with EtOAc
twice. The combined organic layers are washed with water and brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The residue is purified by chromatography on silica gel (elution
DCM/MeOH: 98/2 to 95/5) to afford the expected intermediate.
[1225] LC-MS: MW (calcd): 389; m/z MW (obsd): 390 (M+H)
Step ii)
[1226] To a solution of the above boc protected amine (299.4 mg,
0.77 mmol, 1 eq.) in MeOH (2 mL) is added a 4 M HCl solution in
dioxane (1.9 mL). The reaction mixture is stirred at r.t. for 4 h
then concentrated in vacuo, to afford the expected Intermediate
Gen-10-ac as hydrochloride salt which used directly for the next
step without purification.
[1227] LC-MS: MW (calcd): 289; m/z MW (obsd): 290 (M+H)
2.25. Intermediate Gen-11-j:
2-Chloro-1-(2,5-dimethyl-pyrrolidin-1-yl)-ethanone
##STR00171##
##STR00172##
[1229] To a solution of chloroacetic acid (100 mg, 1.058 mmol, 1
eq.) and 2,5-Dimethyl-pyrrolidine (130 .mu.L, 1.058 mmol, 1 eq.) in
DCM (15 mL) is added DCC resin (14 mg, 2.116 mmol, 2 eq.). The
reaction mixture is stirred at r.t. overnight then filtered. The
resin is washed with MeOH and DCM, and the filtrate is concentrated
in vacuo to afford Intermediate Gen-11-j which used without further
purification in the next step.
TABLE-US-00002 TABLE I Intermediates used towards the compounds of
the invention. MS Int Structures Name Mtd MW Ms`d Gen- 1-a
##STR00173## N-(6-Bromo-2-ethyl- imidazo[1,2- b]pyridazin-3-yl)-
formamide A2 268 (.sup.79Br), 270 (.sup.81Br) 269 (.sup.79Br M +
H), 271 (.sup.81Br M + H) Gen- 1-b ##STR00174## N-(6-Bromo-2-ethyl-
imidazo[1,2-a]pyrazin- 3-yl)-formamide A1 268 (.sup.79Br), 270
(.sup.81Br) 269 (.sup.79Br M + H), 271 (.sup.81Br M + H) Gen- 1-c
##STR00175## N-[6-Bromo-2-((E)- styryl)-imidazo[1,2-
b]pyridazin-3-yl]- formamide A1 342 (.sup.79Br), 344 (.sup.81Br)
343 (.sup.79Br M + H), 345 (.sup.81Br M + H) Gen- 2-a ##STR00176##
N-(6-Bromo-2-ethyl- imidazo[1,2- b]pyridazin-3-yl)-N-
methyl-formamide Gen- 1-a B2 282 (.sup.79Br), 284 (.sup.81Br) 283
(.sup.79Br M + H), 285 (.sup.81Br M + H) Gen- 2-b ##STR00177##
N-(6-Bromo-2-ethyl- imidazo[1,2-a] pyrazin- 3-yl)-N-methyl-
formamide Gen- 1-b B2 282 (.sup.79Br), 284 (.sup.81Br) 283
(.sup.79Br M + H), 285 (.sup.81Br M + H) Gen- 2-c ##STR00178##
N-[6-Bromo-2-((E)- styryl)-imidazo[1,2- b]pyridazin-3-yl]-N-
methyl-formamide Gen- 1-c B1 356 (.sup.79Br), 358 (.sup.81Br) 357
(.sup.79Br M + H), 359 (.sup.81Br M + H) Gen- 3-a ##STR00179##
(6-Bromo-2-ethyl- imidazo[1,2- b]pyridazin-3-yl)- methyl-amine Gen-
2-a C1 254 (.sup.79Br), 256 (.sup.81Br) 255 (.sup.79Br M + H), 257
(.sup.81Br M + H) Gen- 3-b ##STR00180## (6-Bromo-2-ethyl-
imidazo[1,2-a]pyrazin- 3-yl)-methyl-amine Gen- 2-b C2 254
(.sup.79Br), 256 (.sup.81Br) 255 (.sup.79Br M + H), 257 (.sup.81Br
M + H) Gen- 3-c ##STR00181## (E)-N-(6-bromo-2- styrylimidazo[1,2-
b]pyridazin-3-yl)-N- methylamine Gen- 2-c Cl 328 (.sup.79Br), 330
(.sup.81Br); 329 (.sup.79Br M + H), 331 (.sup.81Br M + H) Gen- 4-a
##STR00182## (6-Bromo-2-ethyl- imidazo[1,2- b][pyridazin-3-yl)-[4-
(4-fluoro-phenyl)- thiazol-2-yl]-methyl- amine Gen- 3-a D1 431
(.sup.79Br), 433 (.sup.81Br) 432 (.sup.79Br M + H), 434 (.sup.81Br
M + H) Gen- 4-b ##STR00183## 2-[(6-Bromo-2-ethyl- imidazo[1,2-
b]pyridazin-3-yl)- methyl-amino]-4-(4- fluoro-phenyl)- thiazole-5-
carbonitrile Gen- 3-a D2 456 (.sup.79Br), 458 (.sup.81Br) 457
(.sup.79Br M + H), 459 (.sup.81Br M + H) Gen- 4-c ##STR00184##
[2-[(6-Bromo-2-ethyl- imidazo[1,2- b]pyridazin-3-yl)-
methyl-amino]-4-(4- fluoro-phenyl)-thiazol- 5-yl]-methanol Gen- 4-a
E14 461 (.sup.79Br), 463 (.sup.81Br) 462 (.sup.79Br M + H), 464
(.sup.81Br M + H) Gen- 4-d ##STR00185## 2-[(6-Bromo-2-ethyl-
imidazo[1,2-a]pyrazin- 3-yl)-methyl-amino]- 4-(4-fluoro-phenyl)-
thiazole-5-carbonitrile Gen- 3-b D2 456 (.sup.79Br), 458
(.sup.81Br) 457 (.sup.79Br M + H), 459 (.sup.81Br M + H) Gen- 4-e
##STR00186## 2-{2-[(6-Bromo-2- ethyl-imidazo[1,2- a]pyrazin-3-yl)-
methyl-amino]- thiazol-4-yl}- 5-fluoro- benzonitrile Gen- 3-b D1
456 (.sup.79Br), 458 (.sup.81Br) 457 (.sup.79Br M + H), 459
(.sup.81Br M + H) Gen- 4-f ##STR00187## 2-{6-[(6-Bromo-2-
ethyl-imidazo[1,2- a]pyrazin-3-yl)- methyl-amino]- pyridin-2-yl}-
5-fluoro- benzonitrile Gen- 3-b D2 450 (.sup.79Br), 452 (.sup.81Br)
451 (.sup.79Br M + H), 453 (.sup.81Br, M + H) Gen- 4-g ##STR00188##
2-{2-[(6-Bromo-2- ethyl-imidazo[1,2- b]pyridazin-3-yl)-
methyl-amino]- thiazol-4-yl}- 5-fluoro- benzonitrile Gen- 3-a D1
456 (.sup.79Br), 458 (.sup.81Br) 457 (.sup.79Br M + H), 459
(.sup.81Br M + H) Gen- 4-h ##STR00189## 2-{2-[(6-Bromo-2-
ethyl-imidazo[1,2- a]pyrazin-3-yl)- methyl-amino]-
pyrimidin-4-yl}-5- fluoro-benzamide Gen- 3-b D2 451 (.sup.79Br),
453 (.sup.81Br) 452 (.sup.79Br M + H), 454 (.sup.81Br M + H) Gen-
4-i ##STR00190## [6-Bromo-2-((E)- styryl)-imidazo[1,2-
b]pyridazin-3-yl]-[4- (4-fluoro-phenyl)- thiazol-2-yl]-methyl-
amine Gen- 3-c D1 505 (.sup.79Br), 507 (.sup.81Br) 506 (.sup.79Br M
+ H), 508 (.sup.81Br M + H) Gen- 4-j ##STR00191##
1-(6-bromo-3-((4-(4- fluorophenyl)thiazol- 2-yl) (methyl)amino)
imidazo[1,2-b] pyridazin-2-yl)-2- phenylethane- 1,2-diol Gen- 4-i
See Cpd 195 539 (.sup.79Br), 541 (.sup.81Br) 540 (.sup.79Br M + H),
542 (.sup.81Br M + H) Gen- 4-k ##STR00192## 6-bromo-3-((4-(4-
fluorophenyl)thiazol- 2-yl)(methyl) amino)imidazo
[1,2-b]pyridazine- 2-carbaldehyde Gen- 4-j See Cpd 195 431
(.sup.79Br), 433 (.sup.81Br) 432 (.sup.79Br M + H), 434 (.sup.81Br
M + H) Gen- 4-l ##STR00193## (E)-methyl-3-(6- bromo-3-((4-(4-
fluorophenyl)thiazol- 2-yl)(methyl) amino)imidazo
[1,2-b]pyridazin-2- yl)acrylate Gen- 4-k See cpd 197 487
(.sup.79Br), 489 (.sup.81Br) 488 (.sup.79Br M + H), 490 (.sup.81Br
M + H) Gen- 4-m ##STR00194## N-(6-bromo-2- ethylimidazo[1,2-
b]pyridazin-3-yl)-4- (4-fluoro-2- methylphenyl)-N- methylthiazol-2-
amine Gen- 3-a D1 445 (.sup.79Br), 447 (.sup.81Br) 446 (.sup.79Br M
+ H), 448 (.sup.81Br M + H) Gen- 4-n ##STR00195## (6-Bromo-2-ethyl-
imidazo[1,2-a]pyrazin- 3-yl)-[4-(4-fluoro- phenyl)-thiazol-2-yl]-
methyl-amine Gen- 3-b D1 431 (.sup.79Br), 433 (.sup.81Br) 432
(.sup.79Br M + H), 434 (.sup.81Br M + H) Gen- 4-o ##STR00196##
2-[(6-Bromo-2-ethyl- imidazo[1,2-a]pyrazin- 3-yl)-methyl-amino]-
4-(4-fluoro-phenyl)- pyrimidine-5- carbonitrile Gen- 3-b D2 451
(.sup.79Br), 453 (.sup.81Br) 452 (.sup.79Br M + H), 454 (.sup.81Br
M + H) Gen- 5-a ##STR00197## [2-Ethyl-6-(1,2,3,6-
tetrahydro-pyridin-4- yl)-imidazo[1,2- b]pyridazin-3-yl]-[4-
(4-fluoro-phenyl)- thiazol-2-yl]methyl- amine Cpd 193 E5b 434 435
(M + H) Gen- 5-b ##STR00198## 4-(2-Ethyl-3-{[4-(4-
fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}- imidazo[1,2-
b]pyridazin-6-yl)- [1,4]diazepane-1- carboxylic acid tert- butyl
ester Gen- 4-a E4a 551 552 (M + H) Gen- 5-c ##STR00199##
(6-[1,4]Diazepan-1- yl- 2-ethyl-imidazol[1,2- b]pyridazin-3-yl)-[4-
(4-fluoro-phenyl)- thiazol-2-yl]-methyl- amine Gen- 5-b E5b 451 452
(M + H) Gen- 5-d ##STR00200## [2-Ethyl-6- (hexahydro-
pyrrolo[3,4-c]pyrrol-2- yl)-imidazo[1,2- b]pyridazin-3-yl]-[4-
(4-fluoro-phenyl)- thiazol-2-yl]-methyl- amine Cpd 122 E5b 463 464
(M + H) Gen- 5-e ##STR00201## (1R,4S)-[6-(2,5-Diaza-
bicyclo[2.2.1]hept-2- yl)-2-ethyl- imidazo[1,2-
b]pyridazin-3-yl]-[4- (4-fluoro-phenyl)- thiazol-2-yl]-methyl-
amine Cpd 74 E5b 449 450 (M + H) Gen- 5-f ##STR00202##
{6-[4-(2-Amino- ethyl)-piperazin-1-yl]- 2-ethyl-imidazo[1,2-
b]pyridazin-3-yl}-[4- (4-fluoro-phenyl)- thiazol-2-yl]-methyl-
amine Cpd 56 E5b 480 481 (M + H) Gen- 5-g ##STR00203##
(R)-4-(2-Ethyl-3-{[4- (4-fluoro-phenyl)- thiazol-2-yl]-methyl-
amino}-imidazo[1,2- b]pyridazin-6-yl)-2- hydroxymethyl-
piperazine-1- carboxylic acid tert- butyl ester Gen- 4-a E4b 567
568 (M + H) Gen- 5-h ##STR00204## (R)-[4-(2-Ethyl-3-{[4-
(4-fluoro-phenyl)- thiazol-2-yl]-methyl- amino}-imidazo[1,2-
b]pyridazin-6-yl)- piperazin-2-yl]- methanol Gen- 5-g E5a 467 468
(M + H) Gen- 5-i ##STR00205## 4-(2-Ethyl-3-{[4-(4-
fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}- imidazo[1,2-
b]pyridazin-6-yl)- piperazine-1- carboxylic acid tert- butyl ester
Gen- 4-a E4a or E4b 537 538 (M + H) Gen- 5-j ##STR00206##
(2-Ethyl-6-piperazin- 1-yl-imidazo[1,2- b]pyridazin-3-yl)-[4-
(4-fluoro-phenyl)- thiazol-2-yl]-methyl- amine Gen- 5-i E5b 437 438
(M + H) Gen- 5-k ##STR00207## (2-Ethyl-6-piperidin-4-
yl-imidazo[1,2- b]pyridazin-3-yl)-[4- (4-fluoro-phenyl)-
thiazol-2-yl]-methyl- amine Gen- 5-a E6 436 437 (M + H) Gen- 5-l
##STR00208## Imidazole-1- carboxylic acid [1-(2-
ethyl-3-{[4-(4-fluoro- phenyl)-thiazol-2-yl]- methyl-amino}-
imidazo[1,2- b]pyridazin-6-yl)- piperidin-4-yl]-amide Cpd 82 See
Cpd 89 545 546 (M + H) Gen- 5-m ##STR00209## 2-[4-(3-{[5-Bromo-4-
(4-fluoro-phenyl)- thiazol-2-yl]-methyl- amino}-2-ethyl-
imidazo[1,2- b]pyridazin-6-yl)- piperazin-1-yl]-N,N-
dimethyl-acetamide Cpd 42 E16 600 (.sup.79Br), 602 (.sup.81Br) 601
(.sup.79Br M + H), 603 (.sup.81Br M + H) Gen- 5-n ##STR00210##
4-(3-{[5-Bromo-4-(4- fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}-
2-ethyl-imidazo[1,2- b]pyridazin-6-yl)- piperazine-1- carboxylic
acid tert- butyl ester Gen- 5-i E16 615 (.sup.79Br), 617
(.sup.81Br) 616 (.sup.79Br M + H), 618 (.sup.81Br M + H) Gen- 5-o
##STR00211## 4-(3-{[5-Cyano-4-(4- fluoro-phenyl)-thiazol-
2-yl]-methyl-amino}- 2-ethyl-imidazo[1,2- b]pyridazin-6-yl)-
piperazine-1- carboxylic acid tert- butyl ester Gen- 5-n E17 or
Gen- 4-b E4b 562 563 (M + H) Gen- 5-p ##STR00212## 2-[(2-Ethyl-6-
piperazin-1-yl- imidazo[1,2- b]pyridazin-3-yl)- methyl-amino]-4-(4-
fluoro-phenyl)- thiazole-5-carbonitrile Gen- 5-o E5b 462 463 (M +
H) Gen- 5-q ##STR00213## [5-Bromo-4-(4-fluoro-
phenyl)-thiazol-2-yl]- [2-ethyl-6-(3- morpholin-4-yl-
pyrrolidin-1-yl)- imidazo[1,2- b]pyridazin-3-yl]- methyl-amine Cpd
147 E16 585 (.sup.79Br), 587 (.sup.81Br) 586 (.sup.79Br M + H), 588
(.sup.81Br M + H) Gen- 5-r ##STR00214## [(S)-1-(3-{[5-Cyano-4-
(4-fluoro-phenyl)- thiazol-2-yl]-methyl- amino}-2-ethyl-
imidazo[1,2- b]pyridazin-6-yl)- pyrrolidin-3-yl]- carbamic acid
tert- butyl ester Gen- 4-b E4a 562 563 (M + H) Gen- 5-s
##STR00215## 2-{[6-((S)-3-Amino- pyrrolidin-1-yl)-2-
ethyl-imidazo[1,2- b]pyridazin-3-yl]- methyl-amino}-4-(4-
fluoro-phenyl)- thiazole-5-carbonitrile Gen- 5-r E5b 462 463 (M +
H) Gen- 5-t ##STR00216## [(R)-1-(3-{[5-Cyano- 4-(4-fluoro-phenyl)-
thiazol-2-yl]-methyl- amino}-2-ethyl- imidazo[1,2-
b]pyridazin-6-yl)- pyrrolidin-3-yl]- carbamic acid tert- butyl
ester Gen- 4-b E4a 562 563 (M + H) Gen- 5-u ##STR00217##
2-{[6-((R)-3-Amino- pyrrolidin-1-yl)-2- ethyl-imidazo[1,2-
b]pyridazin-3-yl]- methyl-amino}-4-(4- fluoro-phenyl)-
thiazole-5-carbonitrile Gen- 5-t E5b 462 463 (M + H) Gen- 5-v
##STR00218## (S)-4-(3-{[5-Cyano-4- (4-fluoro-phenyl)-
thiazol-2-yl]-methyl- amino}-2-ethyl- imidazo[1,2-
b]pyridazin-6-yl)-2- hydroxymethyl- piperazine-1- carboxylic acid
tert- butyl ester Gen- 4-b E4b 592 593 (M + H) Gen- 5-w
##STR00219## 2-{[2-Ethyl-6-((S)-3- hydroxymethyl- piperazin-1-yl)-
imidazo[1,2- b]pyridazin-3-yl]- methyl-amino}-4-(4- fluoro-phenyl)-
thiazole-5-carbonitrile Gen- 5-v E5b 492 493 (M + H) Gen- 5-x
##STR00220## 2-({6-[(S)-3-(tert- Butyl-diphenyl- silanyloxymethyl)-
piperazin-1-yl]-2- ethyl-imidazo[1,2- b]pyridazin-3-yl}-
methyl-amino)-4-(4- fluoro-phenyl)- thiazole-5-carbonitrile Gen-
5-w E18 730 731 (M + H) Gen- 5-y ##STR00221##
{6-[(R)-3-(tert-Butyl- diphenyl- silanyloxymethyl)-
piperazin-1-yl]-2- ethyl-imidazo[1,2- b]pyridazin-3-yl}-[4-
(4-fluoro-phenyl)- thiazol-2-yl]-methyl- amine Gen- 5-h E18 705 706
(M + H) Gen- 5-z ##STR00222## [2-Chloromethyl-6-(1-
methanesulfonyl- piperidin-4-yl)- imidazo[1,2-
b]pyridazin-3-yl]-[4- (4-fluoro- phenyl)- thiazol-2-yl]-methyl-
amine Cpd 195 See Cpd 196 532 (.sup.35Cl), 534 (.sup.37Cl) 533
(.sup.35Cl M + H), 535 (.sup.37Cl M + H) Gen- 5-aa ##STR00223##
[6-(3-Amino-azetidin- 1-yl)-2-ethyl- imidazo[1,2-
b]pyridazin-3-yl]-[4- (4-fluoro-phenyl)- thiazol-2-yl]-methyl-
amine Cpd 154 E5a 423 424 (M + H) Gen- 5-ab ##STR00224##
Methanesulfonic acid 1-(2-ethyl-3-{[4-(4- fluoro-phenyl)-thiazol-
2-yl]-methyl-amino}- imidazo[1,2- b]pyridazin-6-yl)-
pyrrolidin-3-yl ester Cpd 129 See Cpd 130 516 517 (M + H) Gen- 5-ac
##STR00225## (S)-4-(2-Ethyl-3-{[4- (4-fluoro-phenyl)-
thiazol-2-yl]-methyl- amino}-imidazo[1,2- b]pyridazin-6-yl)-2-
methoxymethyl- piperazine-1- carboxylic acid tert- butyl ester Cpd
59 See Cpd 62 581 582 (M + H) Gen- 5-ad ##STR00226##
[2-Ethyl-6-((S)-3- methoxymethyl- piperazin-1-yl)- imidazo[1,2-
b]pyridazin-3-yl]-[4- (4-fluoro-phenyl)-
thiazol-2-yl]-methyl- amine Gen- 5-ac E5b 481 482 (M + H) Gen- 5-ae
##STR00227## {6-[(S)-3-(tert-Butyl- diphenyl- silanyloxymethyl)-
piperazin-1-yl]-2- ethyl-imidazo[1,2- b]pyridazin-3-yl}-[4-
(4-fluoro-phenyl)- thiazol-2-yl]-methyl- amine Cpd 60 E18 705 706
(M + H) Gen- 5-af ##STR00228## 4-(2-Ethyl-3-{[4-(4-
fluoro-phenyl)-5- (2,2,2-trifluoro- acetyl)-thiazol-2-yl]-
methyl-amino}- imidazo[1,2- b]pyridazin-6-yl)- piperazine-1-
carboxylic acid tert- butyl ester Gen- 5-i E15 633 634 (M + H) Gen-
5-ag ##STR00229## 1-[2-[(2-Ethyl-6- piperazin-1-yl- imidazo[1,2-
b]pyridazin-3-yl)- methyl-amino]-4-(4- fluoro-phenyl)-thiazol-
5-yl]-2,2,2-trifluoro- ethanone Gen- 5-af E5a 533 534 (M + H) Gen-
5-ah ##STR00230## 4-(3-{[5-Cyano-4-(4- fluoro-phenyl)-thiazol-
2-yl]-methyl-amino}- 2-ethyl-imidazo[1,2- b]pyridazin-6-yl)-3,6-
dihydro-2H-pyridine- 1-carboxylic acid tert- butyl ester Gen- 4-b
E2 459 460 (M + H) Gen- 5-ai ##STR00231## 4-(3-{[5-Cyano-4-(4-
fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}- 2-ethyl-imidazo[1,2-
a]pyrazin-6-yl)- piperidine-1- carboxylic acid tert- butyl ester
Gen- 4-d E3 561 562 (M + H) Gen- 5-aj ##STR00232##
{6-[(S)-3-(tert-Butyl- dimethyl- silanyloxymethyl)-
piperazin-1-yl]-2- ethyl-imidazo[1,2- b]pyridazin-3-yl}-[4-
(4-fluoro-phenyl)- thiazol-2-yl]-methyl- amine Cpd 60 E18 705 706
(M + H) Gen- 5-ak ##STR00233## 2-{6-[(2-Ethyl-6- piperazin-1-yl-
imidazo[1,2-a]pyrazin- 3-yl)-methyl-amino]- pyridin-2-yl}-2-yl}-
5-fluoro- benzonitrile Gen- 4-f Ela 456 457 (M + H) Gen- 5-al
##STR00234## 4-(3-{[5-Cyano-4-(4- fluoro-phenyl)-thiazol-
2-yl]-methyl-amino}- 2-ethyl-imidazo[1,2- a]pyrazin-6-yl)-3,6-
dihydro-2H-pyridine- 1-carboxylic acid tert- butyl ester Gen- 4-d
E2 559 560 (M + H) Gen- 5-am ##STR00235## 2-{[2-Ethyl-6-(1,2,3,6-
tetrahydro-pyridin-4- yl)-imidazo[1,2- a]pyrazin-3-yl]-
methyl-amino}-4-(4- fluoro-phenyl)- thiazole-5-carbonitrile Gen-
5-al E5b 459 460 (M + H) Gen- 5-an ##STR00236## 4-{3-[(3-Bromo-
[1,2,4]thiadiazol-5-yl)- methyl-amino]-2- ethyl-imidzo[1,2-
b]pyridazin-6-yl}- piperidine-1- carboxylic acid tert- butyl ester
Gen- 7-a See Cpd 219 521 (.sup.79Br), 523 (.sup.81Br) 522
(.sup.79Br), 524 (.sup.81Br) Gen- 5-ao ##STR00237##
4-(3-{[3-(2-Cyano-4- fluoro-phenyl)- [1,2,4]thiadiazol-5-yl]-
methyl-amino}-2- ethyl-imidazo[1,2- b]pyridazin-6-yl)-
piperidine-1- carboxylic acid tert- butyl ester Gen- 5-an See Cpd
219 562 563 (M + H) Gen- 5-ap ##STR00238## 4-(3-{[4-(2-Cyano-4-
fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}- 2-ethyl-imidazo[1,2-
b]pyridazin-6-yl)- piperidine-1- carboxylic acid tert- butyl ester
Gen- 7-a D1 561 562 (M + H) Gen- 5-aq ##STR00239##
2-{2-[(2-Ethyl-6- piperidin-4-yl- imidazo[1,2- b]pyridazin-3-yl)-
methyl-amino]- thiazol-4-yl}- 5-fluoro- benzonitrile Gen- 5-ap E5b
461 462 (M + H) Gen- 5-ar ##STR00240## 4-(3-{[4-(2-Cyano-4-
fluoro-phenyl)-5- methyl-thiazol-2-yl]- methyl-amino}-2-
ethyl-imidazo[1,2- b]pyridazin-6-yl)- piperidine-1- carboxylic acid
tert- butyl ester Gen- 7-a D1 575 576 (M + H) Gen- 5-as
##STR00241## 2-{2-[(2-Ethyl-6- piperidin-4-yl- imidazo[1,2-
b]pyridazin-3-yl)- methyl-amino]-5- methyl-thiazol-4-yl}-
5-fluoro-benzonitrile Gen- 5-ar E5b 475 476 (M + H) Gen- 5-at
##STR00242## 4-(3-{[5-Cyano-6-(4- fluoro-phenyl)-
pyridin-2-yl]-methyl- amino}-2-ethyl- imidazo[1,2-
b]pyridazin-6-yl)- piperidine-1- carboxylic acid tert- butyl ester
Gen- 7-a D3 555 556 (M + H) Gen- 5-au ##STR00243## 6-[(2-Ethyl-6-
piperidin-4-yl- imidazo[1,2- b]pyridazin-3-yl)- methyl-amino]-2-(4-
fluoro-phenyl)- nicotinonitrile Gen- 5-at E5b 455 456 (M + H) Gen-
5-av ##STR00244## 4-(3-{[3-Cyano-6-(4- fluoro-phenyl)-
pyridin-2-yl]-methyl- amino}-2-ethyl- imidazo[1,2-
b]pyridazin-6-yl)- piperidine-1- carboxylic acid tert- butyl ester
Gen- 7-a D3 555 556 (M + H) Gen- 5-aw ##STR00245## 2-[(2-Ethyl-6-
piperidin-4-yl- imidazo[1,2- b]pyridazin-3-yl)- methyl-amino]-6-(4-
fluoro-phenyl)- nicotinonitrile Gen- 5-av- E5b 455 456 (M + H) Gen-
5-ax ##STR00246## 4-(2-Ethyl-3-{[6-(4- fluoro-phenyl)-
pyridin-2-yl]-methyl- amino}-imidazo[1,2- b]pyridazin-6-yl)-
piperidine-1- carboxylic acid tert- butyl ester Gen- 7-a D2 530 531
(M + H) Gen- 5-ay ##STR00247## (2-Ethyl-6-piperidin-4-
yl-imidazo[1,2- b]pyridazin-3-yl)-[6- (4-fluoro-phenyl)-
pyridin-2-yl]-methyl- amine Gen- 5-ax E5b 430 431 (M + H) Gen- 5-az
##STR00248## 4-(2-Ethyl-3-{[4-(4- fluoro-phenyl)- pyrimidin-2-yl]-
methyl-amino}- imidazo[1,2- b]pyridazin-6-yl)- piperidine-1-
carboxylic acid tert- butyl ester Gen- 7-a D2 531 532 (M + H) Gen-
5-aaa ##STR00249## (2-Ethyl-6-piperidin-4- yl-imidazo[1,2-
b]pyridazin-3-yl)-[4- (4-fluoro-phenyl)- pyrimidin-2-yl]-
methyl-amine Gen- 5-az E5b 431 432 (M + H) Gen- 5-aab ##STR00250##
4-(3-{[6-(2-Cyano-4- fluoro-phenyl)- pyridin-2-yl]-methyl-
amino}-2-ethyl- imidazo[1,2- b]pyridazin-6-yl)- piperidine-1-
carboxylic acid tert- butyl ester Gen- 7-a D2 555 556 (M + H) Gen-
5-aac ##STR00251## 2-{6-[(2-Ethyl-6- piperidin-4-yl- imidazo[1,2-
b]pyridazin-3-yl)- methyl-amino]- pyridin-2-yl}- 5-fluoro-
benzonitrile Gen- 5-aab E5b 455 456 (M + H) Gen- 5-aad ##STR00252##
4-(2-Ethyl-3-{[2-(4- fluoro-phenyl)- pyrimidin-4-yl]-
methyl-amino}- imidazo[1,2- b]pyridazin-6-yl)- piperidine-1-
carboxylic acid tert- butyl ester Gen- 7-a D3 531 532 (M + H) Gen-
5-aae ##STR00253## (2-Ethyl-6- piperidin-4- yl-imidazo[1,2-
b]pyridazin-3-yl)-[2- (4-fluoro-phenyl)- pyrimidin-4-yl]-
methyl-amine Gen- 5-aad E5b 431 432 (M + H) Gen- 5-aaf ##STR00254##
2-{2-[(2-Ethyl-6- piperazin-1-yl imidazo[1,2-a]pyrazin-
3-yl)-methyl-amino]- pyrimidin-4-yl}-5- fluoro- benzonitrile Gen-
4-h E1a 457 458 (M + H) Gen- 5-aag ##STR00255## 3-((4-(4-
fluorophenyl)thiazol- 2-yl)(methyl)amino)- 6-(1-(methylsylfonyl)-
1,2,3,6- tetrahydropyridin-4- yl)imidazo[1,2- b]pyridazine-2-
carbaldehyde Gen- 4-k E2 512 513 (M + H) Gen- 5-aah ##STR00256##
(E)-methyl-3-(3-((4- (4- fluorophenyl)thiazol- 2-yl)(methyl)amino)-
6-(1-methylsulfonyl)- 1,2,3,6- tetrahydropyridin-4- yl)imidazo[1,2-
b]pyridazin-2- yl)acrylate Gen- 4-l E2 568 569 (M + H) Gen- 5-aai
##STR00257## methyl-3-(3-((4-(4- fluorophenyl)thiazol-
2-yl)(methyl)amino)- 6-(1-methyl- sufonyl)piperidin-
4-yl)imidazo[1,2- b]pyridazin-2- yl)propanoate. Gen- 5-aah E6 572
573 (M + H) Gen- 5-aaj ##STR00258## 3-(3-((4-(4-
fluorophenyl)thiazol- 2-yl)(methyl)amino)- 6-(1-methyl-
sulfonyl)piperidin- 4-yl)imidazo[1,2- b]pyridazin-2- yl)propanoic
acid. Gen- 5-aai See Cpd 197 558 559 (M + H) Gen- 5-aak
##STR00259## (2-Ethyl-6-piperazin- 1-yl-imidazo[1,2-
a]pyrazin-3-yl)-[4-(4- fluoro-phenyl)-thiazol- 2-yl]-methyl-amine
Gen- 4-n E1a 437 438 (M + H) Gen- 5-aal ##STR00260## 2-[(2-Ethyl-6-
piperazin-1-yl- imidazo[1,2-a]pyrazin- 3-yl)-methyl-amino]-
4-(4-fluoro-phenyl)- pyrimidine-5- carbonitrile Gen- 4-o E1a 457
458 (M + H) Cpd 15 ##STR00261## 2-{2-[(2-Ethyl-6- piperazin-1-yl-
imidazo[1,2-a]pyrazin- 3-yl)-methyl-amino]- thiazol-4-yl}-5-fluoro-
benzonitrile Gen- 4-e E1a 462 463 (M + H) Cpd 22 ##STR00262##
2-[(2-Ethyl-6- piperidin-4-yl- imidazo[1,2-a]pyrazin-
3-yl)-methyl-amino]- 4-(4-fluoro-phenyl)- thiazole-5-carbonitrile
Gen- 5-ai E5b 461 462 (M + H) Cpd 42 ##STR00263##
2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol- 2- yl)(methyl)amino)
imidazo[1,2-b] pyridazin-6- yl)piperazin-1-yl)- N,N-
dimethylacetamide Gen- 5-j E8 522 523 (M + H) Cpd 56 ##STR00264##
tert-butyl 2-(4-(2- ethyl-3-((4-(4- fluorophenyl)thiazol- 2-
yl)(methyl)amino) imidazo[1,2-b] pyridazin-6- yl)piperazin-1-
yl)ethylcarbamate Gen- 4-a E4a 580 581 (M + H) Cpd 59 ##STR00265##
(S)-tert-butyl 4-(2- ethyl-3-((4-(4- fluorophenyl)thiazol- 2-
yl)(methyl)amino) imidazo[1,2-b] pyridazin-6- yl)-2-
(hydroxymethyl) piperazine-1- carboxylate Gen- 4-a E4a or E4b 567
568 (M + H) Cpd 60 ##STR00266## (S)-(4-(2-ethyl-3-((4- (4-
fluorophenyl)thiazol- 2- yl)(methyl)amino) imidazo[1,2-b]
pyridazin- 6-yl)piperazin-2- yl)methanol Cpd 59 E5a 467 468 (M + H)
Cpd 74 ##STR00267## tert-butyl-(1R,4S)-5- (2-ethyl-3-((4-(4-
fluorophenyl)thiazol- 2- yl)(methyl)amino) imidazo[1,2-b]
pyridazin-6- yl)-2,5- diazabicyclo[2.2.1] heptane-2- carboxylate
Gen- 4-a E4a 549 550 (M + H) Cpd 75 ##STR00268##
1-((1R,4S)-5-(2-ethyl- 3-((4-(4- fluorophenyl)thiazol- 2-
yl)(methyl)amino) imidazo[1,2-b] pyridazin- 6-yl)-2,5-
diazabicyclo[2.2.1] heptan-2-yl)ethanone Gen- 4-a E4a 491 492 (M +
H) Cpd 81 ##STR00269## tert-butyl 1-(2-ethyl-3- ((4-(4-
fluorophenyl)thiazol- 2- yl)(methyl)amino) imidazo[1,2-b]
pyridazin-6- yl)piperidin-4- ylcarbamate Gen- 4-a E4a or E4b 551
552 (M + H) Cpd 82 ##STR00270## N-(6-(4- aminopiperidin-1-yl)-
2-ethylimidazo[1,2- b]pyridazin-3-yl)-4-(4- fluorophenyl)-N-
methylthiazol-2-amine Cpd 81 E5b 451 452 (M + H) Cpd 95
##STR00271## ethyl 1-(2-ethyl-3-((4- (4- fluorophenyl)thiazol- 2-
yl)(methyl)amino) imidazo[1,2-b] pyridazin- 6-yl)piperidin-4-
carboxylate Gen- 4-a E4a 508 509 (M + H) Cpd 96 ##STR00272##
1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol- 2- yl)(methyl)amino)
imidazo[1,2-b] pyridazin-6- yl)piperidine-4- carboxylic acid Cpd 95
E13 480 481 (M + H) Cpd 100 ##STR00273## [1-(2-Ethyl-3-{[4-(4-
fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}- imidazo[1,2-
b]pyridazin-6-yl)- piperidin-3-ylmethyl]- carbamic acid tert- butyl
ester Gen- 4-a E4a 565 566 (M + H) Cpd 101 ##STR00274## N-(6-(3-
(aminomethyl) piperidin-1-yl)-2- ethylimidazo[1,2-
b]pyridazin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine Cpd
100 E5b 465 466 (M + H) Cpd 122 ##STR00275## tert-butyl
5-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol- 2- yl)(methyl)amino)
imidazo[1,2-b] pyridazin-6- yl)hexahydropyrrolo
[3,4-c]pyrrole-2(1H)- carboxylate Gen- 4-a E4a 563 564 (M + H) Cpd
125 ##STR00276## N-(6-(5-(3- chloropropylsulfonyl)
hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-2- ethylimidazo[1,2-
b]pyridazin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine Gen-
5-d E11 603 (.sup.35Cl), 605 (.sup.37Cl) 604 (.sup.35Cl M + H), 606
(.sup.37Cl M + H) Cpd 129 ##STR00277## 1-(2-ethyl-3-((4-(4-
fluorophenyl)thiazol- 2- yl)(methyl)amino) imidazo[1,2-b]
pyridazin-6- yl)pyrrolidin-3-ol Gen- 4-a E4a 438 439 (M + H) Cpd
133 ##STR00278## tert-butyl 1-(2-ethyl-3- ((4-(4-
fluorophenyl)thiazol- 2- yl)(methyl)amino) imidazo[1,2-b]
pyridazin-6- yl)pyrrolidin-3- ylcarbamate Gen- 4-a E4a 537 538 (M +
H) Cpd 134 ##STR00279## N-(6-(3- aminopyrrolidin-1-yl)-
2-ethylimidazo[1,2- b]pyridazin-3-yl)-4-(4- fluorophenyl)-N-
methylthiazol-2-amine Cpd 133 E5b 437 438 (M + H) Cpd 147
##STR00280## N-(2-ethyl-6-(3- morpholinopyrrolidin-
1-yl)imidazo[1,2- b]pyridazin-3-yl)-4-(4- fluorophenyl)-N-
methylthiazol-2-amine Gen- 4-a E4a 507 508 (M + H) Cpd 154
##STR00281## [1-(2-Ethyl-3-{[4-(4- fluoro-phenyl)-thiazol-
2-yl]-methyl-amino}- imidazo[1,2- b]pyridazin-6-yl)-
azetidin-3-yl]- carbamic acid tert- butyl ester Gen- 4-a E4a or E1b
523 524 (M + H) Cpd 171 ##STR00282## 2-((2-ethyl-6-(3-
hydroxypyrrolidin-1- yl)imidazo[1,2- b]pyridazin-3-
yl)(methyl)amino)-4- (4- fluorophenyl)thiazole- 5-carbonitrile Gen-
4-b E4a 463 464 (M + H) Cpd 193 ##STR00283## tert-butyl
4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol- 2- yl)(methyl)amino)
imidazo[1,2-b] pyridazin-6- yl)-5,6- dihydropyridine-
1(2H)-carboxylate Gen- 4-a E2 534 535 (M + H)
Cpd 195 ##STR00284## (3-((4-(4- fluorophenyl)thiazol-
2-yl)(methyl)amino)- 6-(1-(methylsulfonyl)- 1,2,3,6-
tetrahydropyridin-4- yl)imidazo[1,2- b]pyridazin-2- yl)methanol
Gen- 5-aag See Cpd 195 514 515 (M + H) Gen- 6-a ##STR00285##
4-[2-Ethyl-3-(formyl- methyl-amino)- imidazo[1,2-
b]pyridazin-6-yl]-3,6- dihydro-2H-pyridine- 1-carboxylic acid tert-
butyl ester Gen- 2-a E2 385 386 (M + H) Gen- 6-b ##STR00286##
4-[2-Ethyl-3-(formyl- methyl-amino)- imidazo[1,2-
b]pyridazin-6-yl]- piperidine-1- carboxylic acid tert- butyl ester
Gen- 6-a E6 387 388 (M + H) Gen- 7-a ##STR00287## 4-(2-Ethyl-3-
methylamino- imidazo[1,2- b]pyridazin-6-yl)- piperidine-1-
carboxylic acid tert- butyl ester Gen- 6-b C2 359 360 (M + H) Gen-
8-a ##STR00288## 2-(2-Bromo-acetyl)-5- fluoro-benzonitrile G1 241
(.sup.79Br), 243 (.sup.81Br) 242 (.sup.79Br M + H), 244 (.sup.81Br
M + H) Gen- 8-b ##STR00289## 2-Bromo-1-(2-bromo- 4-fluoro-phenyl)-
ethanone G1 294 296 298 N.A Gen- 8-c ##STR00290## 2-(2-Bromo-
propionyl)-5-fluoro- benzonitrile G1 255 (.sup.79Br), 257
(.sup.81Br) N.A Gen- 9-a ##STR00291## 2-Chloro-4-(4-fluoro-
phenyl)-thiazole-5- carbonitrile G2a 238 (.sup.35Cl), 240
(.sup.37Cl) 239 (.sup.35Cl M + H), 241 (.sup.37Cl M + H) Gen- 9-b
##STR00292## 2-Fluoro-6-(4-fluoro- phenyl)-pyridine G2b 191 192 (M
+ H) Gen- 9-c ##STR00293## 2-Chloro-4-(4-fluoro- phenyl)-pyrimidine
G2b 208 (.sup.35Cl), 210 (.sup.37Cl) 209 (.sup.35Cl M + H), 211
(.sup.37Cl M + H) Gen- 9-d ##STR00294## 5-Fluoro-2-(6-fluoro-
pyridin-2-yl)- benzonitrile G2b 216 217 (M + H) Gen- 9-e
##STR00295## 2-Chloro-4-(4-fluoro- phenyl)-pyrimidine-5-
carbonitrile See Gen- 9-e 233 (.sup.35Cl), 235 (.sup.37Cl) 234
(.sup.35Cl M + H), 236 (.sup.37Cl M + H) Gen- 10-a ##STR00296##
Piperidine-4-sulfonic acid cyclopropylamide See Gen- 10-a 204 N.A
Gen- 10-b ##STR00297## 4-Pyrrolidin-3-yl- thiomorpholine 1,1-
dioxide G3a 204 N.A Gen- 10-c ##STR00298## 1-Pyrrolidin-3-yl-
piperidin-4-ol G3a 170 N.A Gen- 10-d ##STR00299##
3-(1-Pyrrolidin-3-yl- piperidin-4-yl)- propan-1-ol G3a 212 N.A Gen-
10-e ##STR00300## 1-Pyrrolidin-3-yl- piperidine G3a 154 N.A Gen-
10-f ##STR00301## Pyrrolidine-3- carboxylic acid (2-
hydroxy-ethyl)-amide G3b 158 N.A Gen- 10-g ##STR00302##
4-Piperidin-4-yl- morpholine G3a 170 N.A Gen- 10-h ##STR00303##
4-Piperidin-3-yl- morpholine G3a 170 N.A Gen- 10-i ##STR00304##
Morpholin-4-yl- pyrrolidin-3-yl- methanone G3b 184 N.A Gen- 10-j
##STR00305## 1-(2-Piperazin-1-yl- ethyl)-pyrrolidin-2-one See Gen-
10-j 197 N.A Gen- 10-k ##STR00306## 4-Piperidin-3-yl- cyclohexanol
G3a 101 N.A Gen- 10-l ##STR00307## N,N-Dimethyl-2- piperazin-1-yl-
acetamide See Gen- 10-l 171 N.A Gen- 10-m ##STR00308##
N,N-Dimethyl-2- piperidin-4-yl- acetamide G3b 170 N.A Gen- 10-n
##STR00309## 4-Pyrrolidin-3-yl- piperazin-2-one G3a 169 N.A Gen-
10-o ##STR00310## 1-Oxa-3,7-diaza- spiro[4.4]nonan-2-one See Gen-
10-o 142 N.A Gen- 10-p ##STR00311## Azetidin-3-yl- morpholin-4-yl-
methanone G3b 170 N.A Gen- 10-q ##STR00312## Azetidin-3-yl-(3-
hydroxy-pyrrolidin-1- yl)-methanone G3b 170 N.A Gen- 10-r
##STR00313## (3-Hydroxy- pyrrolidin-3- ylmethyl)-carbamic acid
methyl ester G3b 174 N.A Gen- 10-s ##STR00314## N-(3-Hydroxy-
pyrrolidin-3- ylmethyl)-acetamide G3b 158 N.A Gen- 10-t
##STR00315## N-(3-Hydroxy- pyrrolidin-3- ylmethyl)- isobutyramide
G3b 186 N.A Gen- 10-u ##STR00316## (2S,6R)-2,6-Dimethyl-
4-pyrrolidin-3-yl- morpholine G3a 184 185 (M + H) Gen- 10-v
##STR00317## (1-Pyrrolidin-3-yl- piperidin-4-yl)- methanol G3a 184
185 (M + H) Gen- 10-w ##STR00318## 1-(4-Pyrrolidin-3-yl-
piperazin-1-yl)- ethanone G3a 197 198 (M + H) Gen- 10-x
##STR00319## 4-Morpholin-4-yl- pyrrolidin-3-ol See Gen- 10-x 172
173 (M + H) Gen- 10-y ##STR00320## N-Methyl-N-(1- pyrrolidin-3-yl-
piperidin-4-yl)- acetamide G3b + G3a 225 N.A Gen- 10-z ##STR00321##
1-Pyrrolidin-3-yl- piperidin-4-ol G3a 170 N.A Gen- 10-aa
##STR00322## 4-Methoxy-1- pyrrolidin-3-yl- piperidine See Gen-
10-aa 184 N.A Gen- 10-ab ##STR00323## 2-(1-Methanesulfonyl-
piperazin-2-yl)-ethanol See Gen- 10- ab 208 N.A Gen- 10-ac
##STR00324## 1-(4-Methoxy-benzyl)- 3-piperazin-1-yl-
pyrrolidin-2-one See Gen- 10-ac 289 290 (M + H) Gen- 11-a
##STR00325## 2-Chloro-1-(3- hydroxy-azetidin-1- yl)-ethanone G3a
149 (.sup.35Cl), 151 (.sup.37Cl) N.A Gen- 11-b ##STR00326##
2-Chloro-1-(3-fluoro- azetidin-1-yl)- ethanone G3a 151 (.sup.35Cl),
153 (.sup.37Cl) N.A Gen- 11-c ##STR00327## 2-Chloro-1-(3,3-
difluoro-azetidin-1- yl)-ethanone G3a 169 (.sup.35Cl), 170
(.sup.37Cl) 170 (.sup.35Cl M + H) 172 (.sup.37Cl M + H) Gen- 11-d
##STR00328## 1-Azetidin-1-yl-2- chloro-ethanone G3a 133
(.sup.35Cl), 135 (.sup.37Cl) N.A Gen- 11-e ##STR00329##
(S)-2-Chloro-1-(3- hydroxy-pyrrolidin-1- yl)-ethanone G3a 163
(.sup.35Cl), 165 (.sup.37Cl) 164 (.sup.35Cl M + H), 166 (.sup.37Cl
M + H) Gen- 11-f ##STR00330## (R)-2-Chloro-1-(3-
hydroxy-pyrrolidin-1- yl)-ethanone G3b 163 (.sup.35Cl), 165
(.sup.37Cl) 164 (.sup.35Cl M + H), 166 (.sup.37Cl M + H) Gen- 11-g
##STR00331## 2-Chloro-1-(3- hydroxymethyl- pyrrolidin-1-yl)-
ethanone G3c 177 (.sup.35Cl), 178 (.sup.37Cl) N.A Gen- 11-h
##STR00332## 2-Chloro-1-morpholin- 4-yl-ethanone G3b 163
(.sup.35Cl), 165 (.sup.37Cl)) N.A Gen- 11-i ##STR00333##
2-Chloro-N-(3- hydroxy-propyl)- acetamide G3b 151 (.sup.35Cl), 153
(.sup.37Cl) N.A Gen- 11-j ##STR00334## 2-Chloro-1-(2,5-
dimethyl-pyrrolidin-1- yl)-ethanone See Gen- 11-j 174 (.sup.35Cl),
176 (.sup.37Cl) N.A Gen- 11-k ##STR00335## 2-Chloro-1-(3,3-
difluoro-pyrrolidin-1- yl)-ethanone G3c 182 (.sup.35Cl), 184
(.sup.37Cl) N.A Gen- 11-l ##STR00336## 2-Chloro-1-(2-methyl-
pyrrolidin-1-yl)- ethanone G3c 160 (.sup.35Cl), 162 (.sup.37Cl)
N.A
TABLE-US-00003 TABLE II Illustrative compounds of the invention. MS
Cpd Structures Name Mtd MW Ms'd 1 ##STR00337## 2-((2-ethyl-6-
(piperazin-1- yl)imidazo[1,2- a]pyrazin-3- yl)(methyl)amino)- 4-(4-
fluorophenyl)thiazole- 5-carbonitrile Gen-4-d A1-B2- C2-D2- E1a 462
463 (M + H) 2 ##STR00338## 2-((2-ethyl-6-(4-(2- (3-hydroxyazetidin-
1-yl)-2- oxoethyl)piperazin- 1-yl)imidazo[1,2- a]pyrazin-3-
yl)(methyl)amino)- 4-(4- fluorophenyl)thiazole- 5-carbonitrile Cpd
1 A1-B2- C2-D2- E1a-E8 575 576 (M + H) 3 ##STR00339##
2-((6-(4-(2-(3,3- difluoroazetidin-1- yl)-2- oxoethyl)piperazin-
1-yl)-2- ethylimidazo[1,2- a]pyrazin-3- yl)(methyl)amino)- 4-(4-
fluorophenyl)thiazole- 5-carbonitrile Cpd 1 A1-B2- C2-D2- E1a-E8
595 596 (M + H) 4 ##STR00340## 2-((6-(4-(2- (azetidin-1-yl)-2-
oxoethyl)piperazin- 1-yl)-2- ethylimidazo[1,2- a]pyrazin-3-
yl)(methyl)amino)- 4-(4- fluorophenyl)thiazole- 5-carbonitrile Cpd
1 A1-B2- C2-D2- E1a-D2- E1a-E8 559 560 (M + H) 5 ##STR00341##
2-(4-(3-((5-cyano- 4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)-
2-ethylimidazo[1,2- a]pyrazin-6- yl)piperazin-1-yl)- N,N-
dimethylacetamide Cpd 1 A1-B2- C2-D2- E1a-E8 547 548 (M + H) 6
##STR00342## (R)-2-((2-ethyl-6- (4-(2-(3- hydroxypyrrolidin-
1-yl)-2- oxoethyl)piperazin- 1-yl)imidazo[1,2- a]pyrazin-3-
yl)(methyl)amino)- 4-(4- fluorophenyl)thiazole- 5-carbonitrile Cpd
1 A1-B2- C2-D2- E1a-E8 589 590 (M + H) 7 ##STR00343##
(S)-2-((2-ethyl-6- (4-(2-(3- hydroxypyrrolidin- 1-yl)-2-
oxoethyl)piperazin- 1-yl)imidazo[1,2- a]pyrazin-3-
yl)(methyl)amino)- 4-(4- fluorophenyl)thiazole- 5-carbonitrile Cpd
1 A1-B2- C2-D2- E1a-E8 589 590 (M + H) 8 ##STR00344##
2-((2-ethyl-6-(4-(2- oxo-2-(pyrrolidin-1- yl)ethyl)piperazin-
1-yl)imidazo[1,2- a]pyrazin-3- yl)(methyl)amino)- 4-(4-
fluorophenyl)thiazole- 5-carbonitrile Cpd 1 A1-B2- C2-D2- E1a-E8
573 574 (M + H) 9 ##STR00345## 2-(4-(3-((5-cyano- 4-(4-
fluorophenyl)thiazol- 2-yl)(methyl)amino)- 2-ethylimidazo[1,2-
a]pyrazin-6- yl)piperazin-1-yl)- N-methylacetamide Cpd 1 A1-B2-
C2-D2- E1a-E8 533 534 (M + H) 10 ##STR00346## 2-((2-ethyl-6-(4-(2-
morpholino-2- oxoethyl)piperazin-1- yl)imidazo[1,2- a]pyrazin-3-
yl)(methyl)amino)- 4-(4- fluorophenyl)thiazole- 5-carbonitrile Cpd
1 A1-B2- C2-D2- E1a-E8 589 590 (M + H) 11 ##STR00347##
2-((2-ethyl-6-(4-(2- (3-fluoroazetidin-1- yl)-2-
oxoethyl)piperazin- 1-yl)imidazo[1,2- a]pyrazin-3-
yl)(methyl)amino)- 4-(4- fluorophenyl)thiazole- 5-carbonitrile Cpd
1 A1-B2- C2-D2- E1a-E8 577 578 (M + H) 12 ##STR00348##
2-((2-ethyl-6-(4-(2- (3-hydroxyazetidin-1- yl)acetoyl)piperazin-
1-yl)imidazo[1,2- a]pyrazin-3- yl)(methyl)amino)- 4-(4-
fluorophenyl)thiazole- 5-carbonitrile Cpd 1 A1-B2- C2-D2- E1a-
E9b-E8 575 576 (M + H) 13 ##STR00349## 1-(azetidin-1-yl)-2-
(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- a]pyrazin-6- yl)piperazin-1- yl)ethanone Gen-5- aak
A1-B2- C2-D1- E1a-E8 534 535 (M + H) 14 ##STR00350##
2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- a]pyrazin-6- yl)piperazin-1-yl)-1-
(3-hydroxyazetidin-1- yl)ethanone Gen-5- aak A1-B2- C2-D1- E1a-E8
550 551 (M + H) 15 ##STR00351## 2-(2-((2-ethyl-6- (piperazin-1-
yl)imidazo[1,2- a]pyrazin-3- yl)(methyl)amino) thiazol-4-yl)-5-
fluorobenzonitrile Gen-4-e A1-B2- C2-D1- E1a 462 463 (M + H) 16
##STR00352## 2-(2-((2-ethyl-6-(4- (2-(3- hydroxyazetidin-1- yl)-2-
oxoethyl)piperazin- 1-yl)imidazo[1,2- a]pyrazin-3-
yl)(methyl)amino) thiazol-4-yl)-5- fluorobenzonitrile Cpd 15 A1-B2-
C2-D1- E1a-E8 575 576 (M + H) 15 ##STR00353## 2-(6-((2-ethyl-6-(4-
(2-(3- hydroxyazetidin-1- yl)-2- oxoethyl)piperazin-
1-yl)imidazo[1,2- a]pyrazin-3- yl)(methyl)amino) pyridin-2-yl)-5-
fluorobenzonitrile Gen-5- ak A1-B2- C2-D2- E1a-E8 569 570 (M + H)
18 ##STR00354## 2-(2-((2-ethyl-6-(4- (2-(3- hydroxyazetidin-1-
yl)-2- oxoethyl)piperazin-1- yl)imidazo[1,2- a]pyrazin-3-
yl)(methyl)amino) pyrimidin-4-yl)-5- fluorobenzonitrile Gen-5- aaf
A1-B2- C2-D2- E1a-E8 570 571 (M + H) 19 ##STR00355##
2-((2-ethyl-6-(4-(2- (3-hydroxyazetidin- 1-yl)-2-
oxoethyl)piperazin- 1-yl)imidazo[1,2- a]pyrazin-3-
yl)(methyl)amino)- 4-(4-fluorophenyl) pyrimidine-5- carbonitrile
Gen-5- aal A1-B2- C2-D2- E1a-E8 570 571 (M + H) 20 ##STR00356##
2-((2-ethyl-6-(1- (methylsulfonyl)- 1,2,3,6- tetrahydropyridin-
4-yl)imidazo[1,2- a]pyrazin-3- yl)(methyl)amino)- 4-(4-
fluorophenyl)thiazole- 5-carbonitrile Gen-4-d A1-B2- C2-D2- E2 537
538 (M + H) 21 ##STR00357## 2-((2-ethyl-6-(1-(2-
(3-hydroxyazetidin- 1-yl)-2-oxoethyl)- 1,2,3,6- tetrahydropyridin-
4-yl)imidazo[1,2- a]pyrazin-3- yl)(methyl)amino)- 4-(4-
fluorophenyl)thiazole- 5-carbonitrile Gen-5- am A1-B2- C2-D2-
E2-E5b- E8 572 573 (M + H) 22 ##STR00358## 2-((2-ethyl-6-
(piperidin-4- yl)imidazo[1,2- a]pyrazin-3- yl)(methyl)amino)- 4-(4-
fluorophenyl)thiazole- 5-carbonitrile Gen-5- ai A1-B2- C2-D2-
E3-E5b 461 462 (M + H) 23 ##STR00359## 2-((2-ethyl-6-(1-(2-
(3-hydroxyazetidin- 1-yl)-2- oxoethyl)piperidin- 4-yl)imidazo[1,2-
a]pyrazin-3- yl)(methyl)amino)- 4-(4- fluorophenyl)thiazole-
5-carbonitrile Cpd 22 A1-B2- C2-D2- E3-E5b- E8 574 575 (M + H) 24
##STR00360## (R)-2-((2-ethyl-6- (1-(2-(3- hydroxypyrrolidin-
1-yl)-2- oxoethyl)piperidin- 4-yl)imidazo[1,2- a]pyrazin-3-
yl)(methyl)amino)- 4-(4- fluorophenyl)thiazole- 5-carbonitrile Cpd
22 A1-B2- C2-D2- E3-E5b- E8 588 589 (M + H) 25 ##STR00361##
(S)-2-((2-ethyl-6- (1-(2-(3- hydroxypyrrolidin- 1-yl)-2-
oxoethyl)piperidin- 4-yl)imidazo[1,2- a]pyrazin-3-
yl)(methyl)amino)- 4-(4- fluorophenyl)thiazole- 5-carbonitrile Cpd
22 A1-B2- C2-D2- E3-E5b- E8 588 589 (M + H) 26 ##STR00362##
2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperazin-1-yl)-1-
(3-hydroxyazetidin- 1-yl)ethanone Gen-5-j A2-B2- C1-D1- E4b- E5b-E8
550 551 (M + H) 27 ##STR00363## 2-((2-ethyl-6-(4-(2-
(3-hydroxyazetidin- 1-yl)-2- oxoethyl)piperazin- 1-yl)imidazo[1,2-
b]pyridazin-3- yl)(methyl)amino)- 4-(4- fluorophenyl)thiazole-
5-carbonitrile Gen-5-o A2-B2- C1-D1- E4b- E16- E17- E5b-E8 575 576
(M + H) 28 ##STR00364## 2-(4-(2-ethyl-3-((4-(4-
fluorophenyl)thiazole- 2-yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)piperazin-1-yl)- 1-(2- methylpyrrolidin-1-
yl)ethanone Gen-5-j A2-B2- C1-D1- E4b- E5b-E8 562 563 (M + H) 29
##STR00365## 2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-
2-yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-
yl)piperazin-1-yl)-1- (2-(hydroxymethyl) pyrrolidin-1- yl)ethanone
Gen-5-j A2-B2- C1-D1- E4b- E5b-E8 578 579 (M + H) 30 ##STR00366##
2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperazin-1-yl)- N-methylacetamide
Gen-5-j A2-B2- C1-D1- E4b- E5b-E8 508 509 (M + H) 31 ##STR00367##
1-(3,3- difluoropyrrolidin- 1-yl)-2-(4-(2-ethyl- 3-((4-(4-
fluorophenyl)thiazol- 2-yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)piperazin-1- yl)ethanone Gen-5-j A2-B2- C1-D1-
E4b- E5b-E8 584 585 (M + H) 32 ##STR00368## 1-(2,5-
dimethylpyrrolidin- 1-yl)-2-(4-(2-ethyl- 3-((4-(4-
fluorophenyl)thiazol- 2-yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)piperazin-1- yl)ethanone Gen-5-j A2-B2- C1-D1-
E4b- E5b-E8 576 577 (M + H) 33 ##STR00369## (R)-2-(4-(2-ethyl-3-
((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)piperazin-1-yl)- 1-(3- hydroxypyrrolidin-
1-yl)ethanone Gen-5-j A2-B2- C1-D1- E4b- E5b-E8 564 565 (M + H) 34
##STR00370## (S)-2-(4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-
2-yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperazin-1-yl)-
1-(3- hydroxypyrrolidin- 1-yl)ethanone Gen-5-j A2-B2- C1-D1- E4b-
E5b-E8 564 565 (M + H) 35 ##STR00371## 2-(4-(2-ethyl-3-((4-(4-
fluorophenyl)thiazol- 2-yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)piperazin-1-yl)- N-(2-hydroxyethyl) acetamide
Gen-5-j A2-B2- C1-D1- E4b- E5b-E8 538 539 (M + H) 36 ##STR00372##
1-(azetidin-1-yl)-2- (4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-
2-yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperazin-1-
yl)ethanone Gen-5-j A2-B2- C1-D1- E4b- E5b-E8 534 535 (M + H) 37
##STR00373## 2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-
2-yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperazin-1-yl)-
N-isopropyl-N- methylacetamide Gen-5-j A2-B2- C1-D1- E4b- E5b-E8
550 551 (M + H) 38 ##STR00374## N-(2-ethyl-6-(4- (oxetan-3-
yl)piperazin-1- yl)imidazo[1,2- b]pyridazin-3-yl)-4-
(4-fluorophenyl)-N- methylthiazol-2- amine Gen-5-j A2-B2- C1-D1-
E4a- E5b- E10 493 494 (M + H) 39 ##STR00375## N-(2-ethyl-6-(4-
(tetrahydro-2H- pyran-4- yl)piperazin-1- yl)imidazo[1,2-
b]pyridazin-3-yl)-4- (4-fluorophenyl)-N- methylthiazol-2- amine
Gen-5-j A2-B2- C1-D1- E4a- E5b- E10 521 522 (M + H) 40 ##STR00376##
5-((4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperazin-1- yl)methyl)oxazolidin-
2-one Gen-5-j A2-B2- C1-D1- E4b- E5b-E8 536 537 (M + H) 41
##STR00377## 5-((4-(2-ethyl-3- ((4-(4- fluorophenyl)-5-
(hydroxymethyl) thiazol-2-yl)(methyl) amino)imidazo[1,2-
b]pyridazin-6- yl)piperazin-1- yl)methyl)oxazolidin- 2-one Cpd 40
A2-B2- C1-D1- E4b- E5b-E8- E14 566 567 (M + H) 42 ##STR00378##
2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6-yl) piperazin-1-yl)-N,N-
dimethylacetamide Gen-5-j A2-B2- C1-D1- E4b- E5b-E8 522 523 (M + H)
43 ##STR00379## 2-(4-(2-ethyl-3-((4- (4-fluorophenyl)-5-
(hydroxymethyl) thiazol-2-yl)(methyl) amino)imidazo[1,2-
b]pyridazin-6-yl) piperazin-1-yl)-N,N- dimethylacetamide Cpd 42
A2-B2- C1-D1- E4b- E14 552 553 (M + H) 44 ##STR00380##
2-(4-(3-((5-cyano- 4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)-
2-ethylimidazo[1,2- b]pyridazin-6-yl) piperazin-1-yl)-N,N-
dimethylacetamide Gen-5- m A2-B2- C1-D1- E4b- E5b-E8- E16- E17 547
548 (M + H) 45 ##STR00381## 2-(4-(2-ethyl-3-((4-
(4-fluorophenyl)-5- (2,2,2- trifluoroacetoyl) thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-yl)
piperazin-1-yl)-N,N- dimethylacetamide Gen-5- ag A2-B2- C1-D1- E4b-
E15- E5b-E8 618 619 (M + H) 46 ##STR00382## 1-(2-(4-(2-ethyl-3-
((4-(4-fluorophenyl) thiazol-2-yl)(methyl) amino)imidazo[1,2-
b]pyridazin-6- yl)piperazin-1- yl)ethyl)pyrrolidin- 2-one Gen-4-a
A2-B2- C1-D1- E4a 548 549 (M + H) 47 ##STR00383##
(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperazin-1- yl)(tetrahydrofuran-
2-yl)methanone Gen-4-a A2-B2- C1-D1- E4a 435 436 (M + H) 48
##STR00384## N-(2-ethyl-6-(4- ((tetrahydrofuran-2-
yl)methyl)piperazin- 1-yl)imidazo[1,2- b]pyridazin-3-yl)-4-
(4-fluorophenyl)-N- methylthiazol-2- amine Gen-4-a A2-B2- C1-D1-
E4a 521 522 (M + H) 49 ##STR00385## 3-(4-(2-ethyl-3-((4-
(4-fluorophenyl) thiazol-2-yl)(methyl) amino)imidazo[1,2-
b]pyridazin-6- yl)piperazin-1- yl)propan-1-ol Gen-4-a A2-B2- C1-D1-
E4a 495 496 (M + H) 50 ##STR00386## 3-(4-(2-ethyl-3-((4-
(4-fluorophenyl)-5- (hydroxymethyl) thiazol-2-yl)(methyl)
amino)imidazo[1,2- b]pyridazin-6- yl)piperazin-1- yl)propan-1-ol
Cdp 49 A2-B2- C1-D1- E4a- E14 525 526 (M + H) 51 ##STR00387##
3-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperazin-1- yl)propanenitrile
Gen-4-a A2-B2- C1-D1- E4a 490 491 (M + H) 52 ##STR00388##
3-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-
2-yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperazin-1-
yl)propanamide Cpd 51 A2-B2- C1-D1- E4a-see Cpd 52 508 509 (M + H)
53 ##STR00389## N-(2-ethyl-6-(4-(2- methoxyethyl) piperazin-1-
yl)imidazo[1,2- b]pyridazin-3-yl)-4- (4-fluorophenyl)-N-
methylthiazol-2- amine Gen-4-a A2-B2- C1-D1- E4a 495 496 (M + H) 54
##STR00390## 2-(4-(2-ethyl-3-((4- (4-fluorophenyl) thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperazin-1-yl)-
N-isopropylacetamide Gen-4-a A2-B2- C1-D1- E4a 536 537 (M + H) 55
##STR00391## 2-(4-(2-ethyl-3-((4- (4-fluorophenyl)
thiazol-2-yl)(methyl) amino)imidazo[1,2- b]pyridazin-6-
yl)piperazin-1-yl)- 1-(pyrrolidin-1- yl)ethanone Gen-4-a A2-B2-
C1-D1- E4a 548 549 (M + H) 56 ##STR00392## tert-butyl 2-(4-(2-
ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperazin-1- yl)ethylcarbamate
Gen-4-a A2-B2- C1-D1- E4a 580 581 (M + H) 57 ##STR00393##
N-(2-(4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-
2-yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperazin-1-
yl)ethyl)acetamide Gen-5-f A2-B2- C1-D1- E4a- E5b- E9b 522 523 (M +
H) 58 ##STR00394## ethyl 2-(4-(2-ethyl- 3-((4-(4-
fluorophenyl)thiazol- 2-yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)piperazin-1- yl)ethylcarbamate Gen-5-f A2-B2-
C1-D1- E4a- E5b- E9b 552 553 (M + H) 59 ##STR00395## (S)-tert-butyl
4-(2- ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6-yl)-2- (hydroxymethyl) piperazine-1-
carboxylate Gen-4-a A2-B2- C1-D1- E4a 567 568 (M + H) 60
##STR00396## (S)-(4-(2-ethyl-3-((4- (4-fluorophenyl) thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperazin-2-
yl)methanol Cpd 59 A2-B2- C1-D1- E4a-E5a 467 468 (M + H) 61
##STR00397## (S)-7-(2-ethyl-3-((4- (4-fluorophenyl) thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)tetrahydro-1H-
oxazolo[3,4- a]pyrazin-3(5H)-one Cpd 60 A2-B2- C1-D1- E4a- E5a-see
Cpd 61 493 494 (M + H) 62 ##STR00398## (S)-N-(2-ethyl-6-(3-
(methoxymethyl)-4- (methylsulfonyl) piperazin-1- yl)imidazo[1,2-
b]pyridazin-3-yl)-4- (4-fluorophenyl)-N- methylthiazol-2- amine
Gen-5- ad A2-B2- C1-D1- E4b-see Cpd 62- E5b- E11 559 560 (M + H) 63
##STR00399## (S)-(1-(3- (dimethylamino) propylsulfonyl)-4-(2-
ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperazin-2- yl)methanol Gen-5- ae
A2-B2- C1-D1- E4b-E2- E5b- E18- E11- E12- E19 616 617 (M + H) 64
##STR00400## (S)-2-(4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-
2-yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-yl)-2-
(hydroxymethyl) piperazin-1-yl)-1- (pyrrolidin-1- yl)ethanone
Gen-5- ae A2-B2- C1-D1- E4b- E5b- E18-E8- E19 578 579 (M + H) 65
##STR00401## (S)-2-(4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-
2-yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-yl)-2-
(hydroxymethyl) piperazin-1-yl)-1- morpholinoethanone Gen-5- ae
A2-B2- C1-D1- E4b- E5b- E18-E8- E19 594 595 (M + H) 66 ##STR00402##
(S)-8-(2-ethyl-3-((4- (4-fluorophenyl) thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6-yl) hexahydropyrazino[2,1-
c][1,4]oxazin-4(1H)- one Gen-5- ae A2-B2- C1-D1- E4b- E5b- E18-
E9b- E19-See Cpd 66 507 508 (M + H) 67 ##STR00403##
(S)-(4-(2-ethyl-3-((4- (4-fluorophenyl) thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-yl)-1-
(methylsulfonyl) piperazin-2- yl)methanol Gen-5- aj A2-B2- C1-D1-
E4a- E5a- E18- E11- E19 545 546 (M + H) 68 ##STR00404##
(S)-(4-(2-ethyl-3-((4- (4-fluorophenyl)-5- (hydroxymethyl)
thiazol-2- yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-yl)-1-
(methylsulfonyl) piperazin-2- yl)methanol Cpd 67 A2-B2- C1-D1- E4a-
E5a- E18- E11- E19- E14 575 576 (M + H) 69 ##STR00405##
(R)-(4-(2-ethyl-3-((4- (4-fluorophenyl) thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-yl)-1-
(methylsulfonyl) piperazin-2- yl)methanol Gen-5-y A2-B2- C1-D1-
E4b- E5a- E18- E11- E19 545 546 (M + H) 70 ##STR00406##
3-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperazin-1-yl)-1- (4-methoxybenzyl)
pyrrolidin-2-one Gen-4-a A2-B2- C1-D1- E4b 640 641 (M + H) 71
##STR00407## N-(2-ethyl-6-(4- (ethylsulfonyl) piperazin-1-
yl)imidazo[1,2- b]pyridazin-3-yl)-4- (4-fluorophenyl)-N-
methylthiazol-2- amine Gen-4-a A2-B2- C1-D1- E4b 529 530 (M + H) 72
##STR00408## 2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-yl)-1-
(methylsulfonyl) piperazin-2-yl)ethanol Gen-4-a A2-B2- C1-D1- E4b
559 560 (M + H) 73 ##STR00409## 2-(4-(2-ethyl-3-((4-(4- fluoro-2-
methylphenyl)thiazol- 2-yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)piperazin-1-yl)- N,N-dimethylacetamide Gen-4- m
A2-B2- C1-D1- E4b 536 537 (M + H) 74 ##STR00410##
tert-butyl-(1R,4S)- 5-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-yl)-2,5-
diazabicyclo[2.2.1] heptane-2-carboxylate Gen-4-a A2-B2- C1-D1- E4a
549 550 (M + H) 75 ##STR00411## 1-((1R,4S)-5-(2- ethyl-3-((4-(4-
fluorophenyl)thiazol-2- yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6-yl)-2,5- diazabicyclo[2.2.1] heptan-2-yl)ethanone
Gen-5-e A2-B2- C1-D1- E4a- E5b- E9b 491 492 (M + H) 76 ##STR00412##
N-(2-ethyl-6-((1S,4R)- 5-(methylsulfonyl)-2,5- diazabicyclo[2.2.1]
heptan-2- yl)imidazo[1,2- b]pyridazin-3-yl)-4- (4-fluorophenyl)-N-
methylthiazol-2- amine Gen-5-e A2-B2- C1-D1- E4a- E5b- E11 527 528
(M + H) 77 ##STR00413## N-(2-ethyl-6-(3- azaspiro[5.5]undecan-
3-yl)imidazo[1,2- b]pyridazin-3-yl)-4- (4-fluorophenyl)-N-
methylthiazol-2-amine Gen-4-a A2-B2- C1-D1- E4a 504 505 (M + H) 78
##STR00414## N-(2-ethyl-6- morpholinoimidazo[1,2-
b]pyridazin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2- amine
Gen-4-a A2-B2- C1-D1- E4a 438 439 (M + H) 79 ##STR00415##
6-(1,1-Dioxo- thiomorpholin-4- yl)-2-ethyl- imidazo[1,2-
b]pyridazin-3-yl]- [4-(4-fluoro- phenyl)-thiazol-2-
yl]-methyl-amine Gen-4-a A2-B2- C1-D1- E1b 486 487 (M + H) 80
##STR00416## N-(6-(4- (dimethylamino) piperidin-1-yl)-2-
ethylimidazo[1,2- b]pyridazin-3-yl)-4- (4-fluorophenyl)-N-
methylthiazol-2-amine Gen-4-a A2-B2- C1-D1- E4a 479 480 (M + H) 81
##STR00417## tert-butyl 1-(2- ethyl-3-((4-(4- fluorophenyl)thiazol-
2-yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperidin-4-
ylcarbamate Gen-4-a A2-B2- C1-D1- E4a 551 552 (M + H) 82
##STR00418## N-(6-(4- aminopiperidin-1-yl)- 2-ethylimidazo[1,2-
b]pyridazin-3-yl)-4- (4-fluorophenyl)-N- methylthiazol-2- amine Cpd
81 A2-B2- C1-D1- E4a- E5b 451 452 (M + H) 83 ##STR00419##
N-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperidin-4- yl)methanesulfonamide
Cpd 82 A2-B2- C1-D1- E4a- E5b- E11 529 530 (M + H) 84 ##STR00420##
N-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperidin-4- yl)tetrahydro-2H-
pyran-4-carboxamide Cpd 82 A2-B2- C1-D1- E4b- E5b- E9b 563 564 (M +
H) 85 ##STR00421## N-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperidin-4-yl)-2-
hydroxyacetamide Cpd 82 A2-B2- C1-D1- E4b- E5b- E9c 509 510 (M + H)
86 ##STR00422## N-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperidin-4-yl)-
3-methyloxetane-3- carboxamide Cpd 82 A2-B2- C1-D1- E4b- E5b- E9c
549 550 (M + H) 87 ##STR00423## tert-butyl 4-(1-(2- ethyl-3-((4-(4-
fluorophenyl)thiazol-2- yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)piperidin-4- ylcarbamoyl)piperidine-
1-carboxylate Cpd 82 A2-B2- C1-D1- E4b- E5b- E9c 662 663 (M + H) 88
##STR00424## N-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperidin-4-
yl)piperidine-4- carboxamide Cpd 87 A2-B2- C1-D1- E4b- E5b- E9c-
E5b 562 563 (M + H) 89 ##STR00425## N-(1-(2-ethyl-3-((4-(4-
fluorophenyl)thiazol-2- yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)piperidin-4- yl)pyrrolidine-1- carboxamide
Gen-5-1 A2-B2- C1-D1- E4b-see Cpd 89 548 549 (M + H) 90
##STR00426## 1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperidin-4-ol
Gen-4-a A2-B2- C1-D1- E4a 452 453 (M + H) 91 ##STR00427##
1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperidin-3-ol Gen-4-a A2-B2- C1-D1-
E4a 452 453 (M + H) 92 ##STR00428## N-ethyl-2-(1-(2-
ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperidin-3- yloxy)acetamide Gen-4-a
A2-B2- C1-D1- E4a 537 538 (M + H) 93 ##STR00429##
(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-1- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperidin-4- yl)methanol Gen-4-a
A2-B2- C1-D1- E4a 466 467 (M + H) 94 ##STR00430##
(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperidin-3- yl)methanol Gen-4-a
A2-B2- C1-D1- E4a 466 467 (M + H) 95 ##STR00431## 1-(2-Ethyl-3-{[4-
(4-fluoro-phenyl)- thiazol-2-yl]- methyl-amino}- imidazo[1,2-
b]pyridazin-6-yl)- piperidine-4- carboxylic acid ethyl ester
Gen-4-a A2-B2- C1-D1- E4a 508 509 (M + H) 96 ##STR00432##
1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperidine-4- carboxylic acid Cpd 95
A2-B2- C1-D1- E4a- E13 480 481 (M + H) 97 ##STR00433##
1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6-yl)-N-(2- hydroxyethyl)piperidine-
4-caboxamide Cpd 96 A2-B2- C1-D1- E4a- E13- E9a 523 524 (M + H) 98
##STR00434## 1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-
2-yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperidine-4-
carboxamide Gen-4-a A2-B2- C1-D1- E4a 479 480 (M + H) 99
##STR00435## 1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperidine-3-
carboxamide Gen-4-a A2-B2- C1-D1- E4a 479 480 (M + H) 100
##STR00436## [1-(2-Ethyl-3-{[4- (4-fluoro-phenyl)- thiazol-2-yl]-
methyl-amino}- imidazo[1,2- b]pyridazin-6-yl)- piperidin-3-
ylmethyl]-carbamic acid tert-butyl ester Gen-4-a A2-B2- C1-D1- E4a
565 566 (M + H) 101 ##STR00437## N-(6-(3- (aminomethyl)piperidin-
1-yl)-2- ethylimidazo[1,2- b]pyridazin-3-yl)-4- (4-fluorophenyl)-N-
methylthiazol-2- amine Cpd 100 A2-B2- C1-D1- E4a- E5b 465 466 (M +
H) 102 ##STR00438## N-((1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-
2-yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperidin-3-
yl)methyl) methanesulfonamide Cpd 101 A2-B2- C1-D1- E4a- E5b- E11
543 544 (M + H) 103 ##STR00439## [1-(2-Ethyl-3-{[4-
(4-fluoro-phenyl)- thiazol-2-yl]- methyl-amino}- imidazo[1,2-
b]pyridazin-6-yl)- piperidin-4- ylmethyl]-carbamic acid tert-butyl
ester Gen-4-a A2-B2- C1-D1- E4b 565 566 (M + H) 104 ##STR00440##
N-(6-(4- (aminomethyl)piperidin- 1-yl)-2- ethylimidazo[1,2-
b]pyridazin-3-yl)-4- (4-fluorophenyl)-N- methylthiazol-2- amine Cpd
103 A2-B2- C1-D1- E4b- E5b 465 466 (M + H) 105 ##STR00441##
N-((1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-1-
2-yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)piperidin-4-
yl)methyl) methanesulfonamide Cpd 104 A2-B2- C1-D1- E4b- E5b- E11
543 544 (M + H) 106 ##STR00442## 3-((1-(2-ethyl-3-((4-(4-
fluorophenyl)thiazol-2- yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)piperidin-4- yl)methyl)-1,1- dimethylurea Cpd 104
A2-B2- C1-D1- E4b- E5b- E9b 536 537 (M + H) 107 ##STR00443##
N-((1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperidin-4- yl)methyl)tetrahydro-
2H-pyran-4- carboxamide Cpd 104 A2-B2- C1-D1- E4b- E5b- E9b 577 578
(M + H) 108 ##STR00444## 2-(1-(2-ethyl-3-((4-(4-
fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-
yl)piperidin-4-yl)-N,N- dimethylacetamide Gen-4-a A2-B2- C1-D1- E4b
521 522 (M + H) 109 ##STR00445## N-(2-ethyl-6-(4-
morpholinopiperidin- 1-yl)imidazo[1,2- b]pyridazin-3-yl)-4-
(4-fluorophenyl)-N- methylthiazol-2- amine Gen-4-a A2-B2- C1-D1-
E4a 521 522 (M + H) 110 ##STR00446## N-(2-ethyl-6-(3-
morpholinopiperidin- 1-yl)imidazo[1,2- b]pyridazin-3-yl)-4-
(4-fluorophenyl)-N- methylthiazol-2- amine Gen-4-a A2-B2- C1-D1-
E4a 521 522 (M + H) 111 ##STR00447## N-(6-(1,4'-
bipiperidin-1'-yl)-2- ethylimidazo[1,2- b]pyridazin-3-yl)-4-
(4-fluorophenyl)-N- methylthiazol-2- amine Gen-4-a A2-B2- C1-D1-
E4a 519 520 (M + H) 112 ##STR00448## 1'-(2-ethyl-3-((4-(4-
fluorophenyl)thiazol-2- yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6-yl)- 1,3'-bipiperidin-4-ol Gen-4-a A2-B2- C1-D1- E4a
535 536 (M + H) 113 ##STR00449## N-(2-ethyl-6-(4-
phenylpiperidin-1- yl)imidazo[1,2- b]pyridazin-3-yl)-4-
(4-fluorophenyl)-N- methylthiazol-2- amine Gen-4-a A2-B2- C1-D1-
E4a- 512 513 (M + H) 114 ##STR00450## N-cyclopropyl-1-
(2-ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)piperidine-4- sulfonamide Gen-4-a
A2-B2- C1-D1- E4a 555 556 (M + H) 115 ##STR00451##
1-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6-yl)- 1,4-diazepan-1- yl)ethanone Gen-4-a
A2-B2- C1-D1- E4a 493 494 (M + H) 116 ##STR00452## N-(2-ethyl-6-(4-
(methylsulfonyl)- 1,4-diazepan-1- yl)imidazo[1,2-
b]pyridazin-3-yl)-4- (4-fluorophenyl)-N- methylthiazol-2- amine
Gen-5-c A2-B2- C1-D1- E4a- E5b- E11 529 530 (M + H) 117
##STR00453## N-(2-ethyl-6-(8-oxa-2- azaspiro-[4.5]decan-
2-yl)imidazo[1,2- b]pyridazin-3-yl)-4- (4-fluorophenyl)-N-
methylthiazol-2- amine Gen-4-a A2-B2- C1-D1- E1b 492 493 (M + H)
118 ##STR00454## 7-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-yl)-1- oxa-3,7-
diazaspiro[4.4]nonan- 2-one Gen-4-a A2-B2- C1-D1- E4a 493 494 (M +
H) 119 ##STR00455## 7-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-yl)-3-
methyl-1-oxa-3,7- diazaspiro[4.4]nonan- 2-one Gen-4-a A2-B2- C1-D1-
E4a 507 508 (M + H) 120 ##STR00456## 7-(2-ethyl-3-((4-(4-
fluorophenyl)-5- (hydroxymethyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6-yl)-3- methyl-1-oxa-3,7-
diazaspiro[4.4]nonan- 2-one Cpd 119 A2-B2- C1-D1- E4a- E14 537 538
(M + H) 121 ##STR00457## 7-(2-ethyl-3-((4-(4-
fluorophenyl)thiazol-2- yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6-yl)-2,7- diazaspiro[4.4]nonane- 1,3-dione Gen-4-a
A2-B2- C1-D1- E4a 505 506 (M + H) 122 ##STR00458## tert-butyl
5-(2-ethyl-3- ((4-(4-fluorophenyl) thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6-yl) hexahydropyrrolo[3,4-
c]pyrrole-2(1H)- carboxylate Gen-4-a A2-B2- C1-D1- E4a 563 564 (M +
H) 123 ##STR00459## N-(2-ethyl-6-(5- (methylsulfonyl)
hexahydropyrrolo[3,4- c]pyrrol-2(1H)- yl)imidazo[1,2-
b]pyridazin-3-yl)-4- (4-fluorophenyl)-N- methylthiazol-2- amine
Gen-5-d A2-B2- C1-D1- E4a- E5b- E11 541 542 (M + H) 124
##STR00460## 1-(5-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-yl)
hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl) ethanone Gen-5-d A2-B2-
C1-D1- E4a- E5b- E9b 505 506 (M + H) 125 ##STR00461## N-(6-(5-(3-
chloropropylsulfonyl) hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-2-
ethylimidazo[1,2- b]pyridazin-3-yl)-4- (4-fluorophenyl)-N-
methylthiazol-2- amine Gen-5-d A2-B2- C1-D1- E4a- E5b- E11
603(.sup.35Cl), 605(.sup.37Cl) 604(.sup.35Cl M + H), 606(.sup.37Cl
M + H) 126 ##STR00462## N-(6-(5-(3- (dimethylamino) propylsulfonyl)
hexahydropyrrolo[3,4- b]pyrrol-2(1H)-yl)- 2-ethylimidazo[1,2-
b]pyridazin-3-yl)-4- (4-fluorophenyl)-N- methylthiazol-2- amine Cpd
125 A2-B2- C1-D1- E4a- E5b- E11- E12 612 613 (M + H) 127
##STR00463## N-(2-ethyl-6-(5-(3- morpholinopropylsulfonyl)
hexahydropyrrolo[3,4- c]pyrrol-2(1H)- yl)imidazo[1,2-
b]pyridazin-3-yl)-4- (4-fluorophenyl)-N- methylthiazol-2- amine Cpd
125 A2-B2- C1-D1- E4a- E5b- E11- E12 654 655 (M + H) 128
##STR00464## (S)-1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)pyrrolidine-3-
carbonitrile Gen-4-a A2-B2- C1-D1- E4a 447 448 (M + H) 129
##STR00465## 1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)pyrrolidin-3-ol
Gen-4-a A2-B2- C1-D1- E4a 438 439 (M + H) 130 ##STR00466##
1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)pyrrolidin-3-yl formate Cpd 129
A2-B2- C1-D1- E4a-see Cpd 130 466 467 (M + H) 131 ##STR00467##
N-(2-ethyl-6-(3- thiomorpholinopyrrolidin- 1-yl)imidazo[1,2-
b]pyridazin-3-yl)-4- (4-fluorophenyl)-N- methylthiazol-2- amine Cpd
129 A2-B2- C1-D1- E4a-E7- E10 523 524 (M + H) 132 ##STR00468##
1-(3-((5-chloro-4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)-2-
ethylimidazo[1,2- b]pyridazin-6- yl)pyrrolidin-3-one Cpd 129 A2-B2-
C1-D1- E4a-see Cpd 132 470(.sup.35Cl), 472(.sup.37Cl) 471(.sup.35Cl
M + H), 473 (.sup.37Cl M + H) 133 ##STR00469## tert-butyl 1-(2-
ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)pyrrolidin-3- ylcarbamate Gen-4-a
A2-B2- C1-D1- E4a- 537 538 (M + H) 134 ##STR00470## N-(6-(3-
aminopyrrolidin-1-yl)-2- ethylimidazo[1,2- b]pyridazin-3-yl)-4-
(4-fluorophenyl)-N- methylthiazol-2- amine Cpd 133 A2-B2- C1-D1-
E4a- E5b 437 438 (M + H) 135 ##STR00471## methyl
2-(1-(2-ethyl-3-((4- (4-fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)pyrrolidin-3- ylamino)acetate Cpd
134 A2-B2- C1-D1- E4a- E5b- E8 509 510 (M + H) 136 ##STR00472##
N-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)pyrrolidin-3-yl)-2- hydroxyacetamide
Cpd 134 A2-B2- C1-D1- E4a- E5b-E9c 495 496 (M + H) 137 ##STR00473##
N-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)pyrrolidin-3- yl)methanesulfonamide
Cpd 134 A2-B2- C1-D1- E4a- E5b- E11 515 516 (M + H) 138
##STR00474## (S)-1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)pyrrolidine-2-
carboxylic acid Gen-4-a A2-B2- C1-D1- see Cpd 138 466 467 (M + H)
139 ##STR00475## 1-(2-Ethyl-3-{[4-(4- fluoro-phenyl)-thiazol-
2-yl]-methyl-amino}- imidazo[1,2- b]pyridazine-6-yl)-
pyrrolidine-3- carboxylic acid methyl ester Gen-4-a A2-B2- C1-D1-
E4a 480 481 (M + H) 140 ##STR00476## 1-(2-ethyl-3-((4-(4-
fluorophenyl)thiazol-2- yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6-yl)-N-(2- hydroxyethyl)pyrrolidine- 3-carboxamide
Gen-4-a A2-B2- C1-D1- E4a 509 510 (M + H) 141 ##STR00477##
(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)pyrrolidin-3-
yl)(morpholino)methanone Gen-4-a A2-B2- C1-D1- E4a 535 536 (M + H)
142 ##STR00478## (1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)pyrrolidin-2-
yl)methanol Gen-4-a A2-B2- C1-D1- E4a 452 453 (M + H) 143
##STR00479## (1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)pyrrolidin-3-
yl)methanol Gen-4-a A2-B2- C1-D1- E4a 452 453 (M + H) 144
##STR00480## (1-(2-ethyl-3-((4-(4- fluorophenyl)-5-
(hydroxymethyl)thiazol-2- yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)pyrrolidin-3- yl)methanol Cpd 143 A2-B2- C1-D1-
E4a-E14 482 483 (M + H) 145 ##STR00481## 3-(4-(1-(2-ethyl-3-((4-(4-
fluorophenyl)thiazol-2- yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)pyrrolidin-3- yl)piperazin-1- yl)propan-1-ol
Gen-4-a A2-B2- C1-D1- E4a 564 565 (M + H) 146 ##STR00482##
4-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)pyrrolidin-3- yl)piperazin-2-one
Gen-4-a A2-B2- C1-D1- E4a 520 521 (M + H) 147 ##STR00483##
N-(2-ethyl-6-(3- morpholinopyrrolidin-1- yl)imidazo[1,2-
b]pyridazin-3-yl)-4- (4-fluorophenyl)-N- methylthiazol-2- amine
Gen-4-a A2-B2- C1-D1- E4a 507 508 (M + H) 148 ##STR00484##
(2-((2-ethyl-6-(3- morpholinopyrrolidin-1- yl)imidazo[1,2-
b]pyridazin-3- yl)(methyl)amino)-4-(4- fluorophenyl)thiazol-5-
yl)methanol Cpd 147 A2-B2- C1-D1- E4a-E14 537 538 (M + H) 149
##STR00485## 2-((2-ethyl-6-(3- morpholinopyrrolidin-1-
yl)imidazo[1,2- b]pyridazin-3- yl)(methyl)amino)-4-(4-
fluorophenyl)thiazole-5- carbonitrile Gen-5-q A2-B2- C1-D1- E4a-
E16- E17 532 533 (M + H) 150 ##STR00486## {6-[3-(1,1-Dioxo-
thiomorpholin-4- yl)-pyrrolidin-1-yl]- 2-ethyl-imidazo[1,2-
b]pyridazin-3-yl}- [4-(4-fluoro-phenyl)- thiazol-2-yl]-methyl-
amine Gen-4-a A2-B2- C1-D1- E4a 555 556 (M + H) 151 ##STR00487##
N-(2-ethyl-6-(3- (piperidin-1-yl)pyrrolidin- 1-yl)imidazo[1,2-
b]pyridazin-3-yl)-4- (4-fluorophenyl)-N- methylthiazol-2-amine
Gen-4-a A2-B2- C1-D1- E4a 505 506 (M + H) 152 ##STR00488##
1-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)pyrrolidin-3- yl)piperidin-4-ol
Gen-4-a A2-B2- C1-D1- E4a 521 522 (M + H) 153 ##STR00489##
(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)azetidin-3- yl)methanol Gen-4-a
A2-B2- C1-D1- E4a 438 439 (M + H) 154 ##STR00490##
[1-(2-Ethyl-3-{[4-(4- fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}-
imidazo[1,2-b]pyridazin- 6-yl)-azetidin-3-yl]- carbamic acid tert-
butyl ester Gen-4-a A2-B2- C1-D1- E4a 523 524 (M + H) 155
##STR00491## 2-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)azetidin-3-
ylamino)-1-(3- hydroxyazetidin-1- yl)ethanone Gen-5- aa A2-B2-
C1-D1- E4a E5a-E8 536 537 (M + H) 156 ##STR00492##
2-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)azetidin-3- ylamino)-N,N-
dimethylacetamide Gen-5- aa A2-B2- C1-D1- E1b- E5a-E8 508 509 (M +
H) 157 ##STR00493## 2-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6- yl)azetidin-3-
ylamino)-N- methylacetamide Gen-5- aa A2-B2- C1-D1- E1b- E5a-E8 494
495 (M + H) 158 ##STR00494## N-(1-(2-ethyl-3-((4-(4-
fluorophenyl)thiazol-2- yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)azetidin-3- yl)methanesulfonamide Gen-5- aa
A2-B2- C1-D1- E4a- E5a-E11 501 502 (M + H) 159 ##STR00495##
(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)azetidin-3-yl)(3- hydroxypyrrolidin-
1-yl)methanone Gen-4-a A2-B2- C1-D1- E4b 521 522 (M + H) 160
##STR00496## 2-((2-ethyl-6-(4- ((2-oxooxazolidin-5-
yl)methyl)piperazin-1- yl)imidazo[1,2- b]pyridazin-3-
yl)(methyl)amino)- 4-(4- fluorophenyl)thiazole-5- carbonitrile
Gen-5-p A2-B2- C1-D2- E4b- E5b-E8 561 562 (M + H) 161 ##STR00497##
(S)-2-((2-ethyl-6-(3- (hydroxymethyl)-4- (methylsulfonyl)piperazin-
1-yl)imidazo[1,2- b]pyridazin-3- yl)(methyl)amino)-4-(4-
fluorophenyl)thiazole-5- carbonitrile Gen-5-x A2-B2- C1-D2- E4b-
E5b E18- E11- E19 570 571 (M + H) 162 ##STR00498##
2-((2-ethyl-6-(2-oxo-1- oxa-3,7-diazaspiro[4.5]
decan-7-yl)imidazo[1,2- b]pyridazin-3- yl)(methyl)amino)-4-(4-
fluorophenyl)thiazole-5- carbonitrile Gen-4-b A2-B2- C1-D2- E4a 532
533 (M + H) 163 ##STR00499## 2-((2-ethyl-6-(3-methyl-
2-oxo-1-oxa-3,7- diazaspiro[4.5]decan-7- yl)imidazo[1,2-
b]pyridazin-3- yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-
5-carbonitrile Gen-4-b A2-B2- C1-D2- E4a 546 547 (M + H) 164
##STR00500## 2-((2-ethyl-6-(3-methyl- 2-oxo-1-oxa-3,7-
diazaspiro[4.4]nonan-7- yl)imidazo[1,2- b]pyridazin-3-
yl)(methyl)amino)-
4-(4-fluorophenyl) thiazole-5-carbonitrile Gen-4-b A2-B2- C1-D2-
E4a 532 533 (M + H) 165 ##STR00501## tert-butyl 7-(3-((5-cyano-
4-(4-fluorophenyl)thiazol- 2-yl)(methyl)amino)-2- ethylimidazo[1,2-
b]pyridazin-6-yl)-2,7- diazaspiro[4.4]nonane- 2-carboxylate Gen-4-b
A2-B2- C1-D2- E4a 602 603 (M + H) 166 ##STR00502##
2-((2-ethyl-6-(2,7- diazaspiro[4.4]nonan-2- yl)imidazo[1,2-
b]pyridazin-3- yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5-
carbonitrile Cpd 165 A2-B2- C1-D2- E4a-E5b 502 503 (M + H) 167
##STR00503## 2-((6-(7-acetoyl-2,7- diazaspiro[4.4]nonan-2-
yl)-2-ethylimidazo[1,2- b]pyridazin-3-yl)(methyl)
amino)-4-(4-fluorophenyl) thiazole-5-carbonitrile Cpd 166 A2-B2-
C1-D2- E4a- E5b- E9b 544 545 (M + H) 168 ##STR00504## methyl
(1-(3-((5-cyano-4- (4-fluorophenyl)thiazol-2- yl)(methyl)amino)-2-
ethylimidazo[1,2- b]pyridazin-6-yl)-3- hydroxypyrrolidin-3-yl)
Gen-4-b A2-B2- C1-D2- E4a 550 551 (M + H) 169 ##STR00505##
N-((1-(3-((5-cyano-4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino)-2- ethylimidazo[1,2- b]pyridazin-6-yl)-3-
hydroxypyrrolidin-3- yl)methyl)acetamide Gen-4-b A2-B2- C1-D2- E4a
534 535 (M + H) 170 ##STR00506## N-((1-(3-((5-cyano-4-(4-
fluorophenyl)thiazol-2- yl)(methyl)amino)- 2-ethylimidazo[1,2-
b]pyridazin-6-yl)-3- hydroxypyrrolidin-3- yl)methyl)isobutyramide
Gen-4-b A2-B2- C1-D2- E4a 562 563 (M + H) 171 ##STR00507##
2-((2-ethyl-6-(3- hydroxypyrrolidin-1- yl)imidazo[1,2-
b]pyridazin-3- yl)(methyl)amino)- 4-(4-fluorophenyl)
thiazole-5-carbonitrile Gen-4-b A2-B2- C1-D2- E4a 463 464 (M + H)
172 ##STR00508## 2-((2-ethyl-6-(3- oxopyrrolidin-1- yl)imidazo[1,2-
b]pyridazin-3- yl)(methyl)amino)-4- (4-fluorophenyl)thiazole-
5-carbonitrile Cpd 171 A2-B2- C1-D2- E4a-E7 461 462 (M + H) 173
##STR00509## 2-((2-ethyl-6-(3- (hydroxymethyl) pyrrolidin-1-
yl)imidazo[1,2- b]pyridazin-3- yl)(methyl)amino)-
4-(4-fluorophenyl) thiazole-5-carbonitrile Gen-4-b A2-B2- C1-D2-
E4a 477 478 (M + H) 174 ##STR00510## (S)-2-((2-ethyl-6-(3-(2-(3-
hydroxyazetidin-1-yl)-2- oxoethylamino)pyrrolidin-
1-yl)imidazo[1,2- b]pyridazin-3- yl)(methyl)amino)-4-(4-
fluorophenyl)thiazole-5- carbonitrile Gen-5-s A2-B2- C1-D2- E4a-
E5b-E8 575 576 (M + H) 175 ##STR00511## (S)-2-(1-(3-((5-cyano-
4-(4-fluorophenyl)thiazol- 2-yl)(methyl)amino)-2- ethylimidazo[1,2-
b]pyridazin-6- yl)pyrrolidin-3- ylamino)-N,N- dimethylacetamide
Gen-5-s A2-B2- C1-D2- E4a- E5b-E8 547 548 (M + H) 176 ##STR00512##
(R)-2-((2-ethyl-6-(3-(2-(3- hydroxyazetidin-1-yl)-2-
oxoethylamino)pyrrolidin- 1-yl)imidazo[1,2- b]pyridazin-3-
yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5- carbonitrile
Gen-5-u A2-B2- C1-D2- E4a- E5b-E8 575 576 (M + H) 177 ##STR00513##
(R)-2-(1-(3-((5-cyano-4- (4-fluorophenyl)thiazol-2-
yl)(methyl)amino)-2- ethylimidazo[1,2- b]pyridazin-6-
yl)pyrrolidin-3- ylamino)-N,N- dimethylacetamide Gen-5-u A2-B2-
C1-D2- E4a- E5b-E8 547 548 (M + H) 178 ##STR00514##
2-((6-(3-((2S,6R)-2,6- dimethylmorpholino) pyrrolidin-1-yl)-2-
ethylimidazo[1,2- b]pyridazin-3- yl)(methyl)amino)-4-(4-
fluorophenyl)thiazole- 5-carbonitrile Gen-4-b A2-B2- C1-D2- E4b 560
561 (M + H) 179 ##STR00515## 2-((2-ethyl-6-(3-(4-
(hydroxymethyl)piperidin- 1-yl)pyrrolidin-1- yl)imidazo[1,2-
b]pyridazin-3- yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5-
carbonitrile Gen-4-b A2-B2- C1-D2- E4b 560 561 (M + H) 180
##STR00516## 2-((6-(3-(4- acetoylpiperazin-1- yl)pyrrolidin-1-yl)-
2-ethylimidazo[1,2- b]pyridazin-3- yl)(methyl)amino)-4-
(4-fluorophenyl)thiazole- 5-carbonitrile Gen-4-b A2-B2- C1-D2- E4b-
573 574 (M + H) 181 ##STR00517## N-(1-(1-(3-((5-cyano-4-
(4-fluorophenyl)thiazol- 2-yl)(methyl)amino)-2- ethylimidazo[1,2-
b]pyridazin-6- yl)pyrrolidin-3- yl)piperidin-4-yl)-
N-methylacetamide Gen-4-b A2-B2- C1-D2- E4b 601 602 (M + H) 182
##STR00518## 2-((2-ethyl-6-(3-(4- hydroxypiperidin-1-
yl)pyrrolidin-1-yl) imidazo[1,2-b]pyridazin- 3-yl)(methyl)amino)-4-
(4-fluorophenyl)thiazole- 5-carbonitrile Gen-4-b A2-B2- C1-D2- E4b
546 547 (M + H) 183 ##STR00519## 2-((2-ethyl-6-(3-(4-
methoxypiperidin-1- yl)pyrrolidin-1-yl) imidazo[1,2-b]pyridazin-
3-yl)(methyl)amino)-4- (4-fluorophenyl)thiazole- 5-carbonitrile
Gen-4-b A2-B2- C1-D2- E4b 560 561 (M + H) 184 ##STR00520##
2-((2-ethyl-6-((3S,4S)- 3-hydroxy-4- morpholinopyrrolidin-
1-yl)imidazo[1,2- b]pyridazin-3- yl)(methyl)amino)-4-
(4-fluorophenyl)thiazole- 5-carbonitrile Gen-4-b A2-B2- C1-D2- E4b
548 549 (M + H) 185 ##STR00521## 1-(2-ethyl-3-((4-(4-
fluorophenyl)-5- (hydroxymethyl)thiazol- 2-yl)(methyl)amino)
imidazo[1,2- b]pyridazin-6- yl)pyrrolidin-3-ol Gen-4-c A2-B2-
C1-D1- E14-E4a 468 469 (M + H) 186 ##STR00522##
(2-((2-ethyl-6-(8-oxa- 2-azaspiro[4.5]decan-2- yl)imidazo[1,2-
b]pyridazin-3- yl)(methyl)amino)-4- (4-fluorophenyl)thiazol-
5-yl)methanol Gen-4-c A2-B2- C1-D1- E14-E4a 522 523 (M + H) 187
##STR00523## [1-(3-{[5-Cyano-4-(4- fluoro-phenyl)-thiazol-2-
yl]-methyl-amino}-2- ethyl-imidazo[1,2- b]pyridazin-6-yl)-
azetidin-3-yl]-carbamic acid tert-butyl ester Gen-4-b A2-B2- C1-D2-
E1b 548 549 (M + H) 188 ##STR00524## 2-((6-(3-aminoazetidin-
1-yl)-2-ethylimidazo[1,2- b]pyridazin-3-yl)(methyl)
amino)-4-(4-fluorophenyl) thiazole-5-carbonitrile Cpd 187 A2-B2-
C1-D2- E1b-E5a 448 449 (M + H) 189 ##STR00525##
2-((2-ethyl-6-(3-(2-(3- hydroxyazetidin-1-yl)-2-
oxoethylamino)azetidin- 1-yl)imidazo[1,2- b]pyridazin-3-yl)(methyl)
amino)-4-(4-fluorophenyl) thiazole-5-carbonitrile Cpd 188 A2-B2-
C1-D2- E1b- E5a-E8 561 562 (M + H) 190 ##STR00526##
N-(1-(3-((5-cyano-4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino)-2- ethylimidazo[1,2- b]pyridazin-6-
yl)azetidin-3- yl)methanesulfonamide Cpd 188 A2-B2- C1-D2- E1b-
E5a-E11 526 527 (M + H) 191 ##STR00527## 2-((2-ethyl-6-(3-
(morpholine-4- carbonyl)azetidin-1-yl) imidazo[1,2-b]pyridazin-
3-yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5- carbonitrile
Gen-4-b A2-B2- C1-D2- E4a 546 547 (M + H) 192 ##STR00528##
2-((2-ethyl-6-(3-(3- hydroxypyrrolidine-1- carbonyl)azetidin-1-yl)
imidazo[1,2-b]pyridazin- 3-yl)(methyl)amino)-4-
(4-fluorophenyl)thiazole- 5-carbonitrile Gen-4-b A2-B2- C1-D2- E4a
546 547 (M + H) 193 ##STR00529## 4-(2-Ethyl-3-{[4-(4-
fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}-
imidazo[1,2-b]pyridazin- 6-yl)-3,6-dihydro-2H-
pyridine-1-carboxylic acid tert-butyl ester Gen-4-a A2-B2- C1-D1-
E2 534 535 (M + H) 194 ##STR00530## N-(2-ethyl-6-(1-
(methylsulfonyl)-1,2,3,6- tetrahydropyridin-4-yl)
imidazo[1,2-b]pyridazin- 3-yl)-4-(4-fluorophenyl)-
N-methylthiazol-2-amine Gen-5-a A2-B2- C1-D1- E2-E5b- E11 512 513
(M + H) 195 ##STR00531## (3-((4-(4-fluorophenyl)
thiazol-2-yl)(methyl) amino)-6-(1- (methylsulfonyl)-1,2,3,6-
tetrahydropyridin-4-yl) imidazo[1,2-b]pyridazin- 2-yl)methanol
Gen-5- aag A1-B1- C1-D1- see Cpd 195-E2- see Cpd 195 514 515 (M +
H) 196 ##STR00532## 2-(3-((4-(4-fluorophenyl) thiazol-2-yl)(methyl)
amino)-6-(1- (methylsulfonyl)-1,2,3,6- tetrahydropyridin-4-yl)
imidazo[1,2-b]pyridazin- 2-yl)acetonitrile Gen-5-z A1-B1- C1-D1-
see Cpd 195-E2- See Cpd 196 523 524 (M + H) 197 ##STR00533##
3-(3-((4-(4-fluorophenyl) thiazol-2-yl)(methyl) amino)-6-(1-
(methylsulfonyl)piperidin- 4-yl)imidazo[1,2- b]pyridazin-2-yl)
propanamide Gen-5- aaj A1-B1- C1-D1- See Cpd 197-E2- E6-See Cpd 197
557 558 (M + H) 198 ##STR00534## 3-(3-((4-(4-fluorophenyl)
thiazol-2-yl)(methyl) amino)-6-(1- (methylsulfonyl)piperidin-
4-yl)imidazo[1,2- b]pyridazin-2- yl)propanenitrile Cpd 197 A1-B1-
C1-D1- See Cpd 197-E2- E6-See Cpd 197-See Cpd 198 539 540 (M + H)
199 ##STR00535## 3-(3-((4-(4-fluorophenyl)-
5-(2,2,2-trifluoroacetoyl) thiazol-2-yl)(methyl) amino)-6-(1-
(methylsulfonyl)piperidin- 4-yl)imidazo[1,2- b]pyridazin-2-
yl)propanenitrile Cpd 197 A1-B1- C1-D1- see Cpd 199-E2- E6-see Cpd
199 635 636 (M + H) 200 ##STR00536## 3-(3-((4-(4-fluorophenyl)
thiazol-2-yl)(methyl) amino)-6-(1- (methylsulfonyl)piperidin-
4-yl)imidazo[1,2- b]pyridazin-2- yl)propan-1-ol Gen-5- aaj A1-B1-
C1-D1- See Cpd 197-E2- E6-see Cpd 197- See Cpd 200 544 545 (M + H)
201 ##STR00537## 2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-
yl)(methyl)amino) imidazo[1,2- b]pyridazin-6-
yl)piperidin-1-yl)-1-(3- hydroxyazetidin-1- yl)ethanone Gen-5-k
A2-B2- C1-D1- E2-E5b- E6-E8 549 550 (M + H) 202 ##STR00538##
2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)
imidazo[1,2-b]pyridazin- 6-yl)piperidin-1-yl)-N,N-
dimethylacetamide Gen-5-k A2-B2- C1-D1- E2-E5b- E6-E8 521 522 (M +
H) 203 ##STR00539## 2-(4-(2-ethyl-3-((4-(4- fluorophenyl)-5-
(hydroxymethyl)thiazol- 2-yl)(methyl)amino) imidazo[1,2-
b]pyridazin-6- yl)piperidin-1-yl)-N,N- dimethylacetamide Cpd 202
A2-B2- C1-D1- E2-E5b- E6-E8- E14 551 552 (M + H) 204 ##STR00540##
2-(2-((2-ethyl-6-(1- (methylsulfonyl)-1,2,3,6-
tetrahydropyridin-4-yl) imidazo[1,2-b]pyridazin-
3-yl)(methyl)amino) thiazol-4-yl)-5- fluorobenzonitrile Gen-4-g
A2-B2- C1-D1- E2 537 538 (M + H) 205 ##STR00541##
2-(2-((2-ethyl-6-(1- (methylsulfonyl)piperidin- 4-yl)imidazo[1,2-
b]pyridazin-3- yl)(methyl)amino)thiazol- 4-yl)-5-fluorobenzonitrile
Cpd 204 A2-B2- C1-D1- E2-E6 539 540 (M + H) 206 ##STR00542##
2-(2-((2-ethyl-6-(1- (methylsulfonyl)piperidin- 4-yl)imidazo[1,2-
b]pyridazin-3-yl)(methyl) amino)-5-(hydroxymethyl) thiazol-4-yl)-5-
fluorobenzonitrile Cpd 205 A2-B2- C1-D1- E2-E6- E14 569 570 (M + H)
207 ##STR00543## 2-(2-((2-ethyl-6-(1-(2-(3-
hydroxyazetidin-1-yl)-2- oxoethyl)piperidin-4-yl)
imidazo[1,2-b]pyridazin- 3-yl)(methyl)amino) thiazol-4-yl)-5-
fluorobenzonitrile Gen-5- aq A2-B2- E2-E6- C2-D1- E5b-E8 574 575 (M
+ H) 208 ##STR00544## 2-(4-(3-((4-(2-cyano-4-
fluorophenyl)thiazol-2- yl)(methyl)amino)-2- ethylimidazo[1,2-
b]pyridazin-6-yl)piperidin- 1-yl)-N,N- dimethylacetamide Gen-5- aq
A2-B2- E2-E6- C2-D1- E5b-E8 546 547 (M + H) 209 ##STR00545##
2-(4-(3-((4-(2-cyano-4- fluorophenyl)thiazol-2-
yl)(methyl)amino)-2- ethylimidazo[1,2- b]pyridazin-6-
yl)piperidin-1-yl)- N-methylacetamide Gen-5- aq A2-B2- E2-E6-
C2-D1- E5b-E8 532 533 (M + H) 210 ##STR00546##
2-(2-((2-ethyl-6-(1-(2-(3- hydroxyazetidin-1-yl)-2-
oxoethyl)piperidin-4-yl) imidazo[1,2-b]pyridazin-
3-yl)(methyl)amino)-5- methylthiazol-4-yl)-5- fluorobenzonitrile
Gen-5- as A2-B2- E2-E6- C2-D1- E5b-E8 588 589 (M + H) 211
##STR00547## 2-(4-(3-((4-(2-cyano-4- fluorophenyl)-5-
methylthiazol-2-yl) (methyl)amino)-2- ethylimidazo[1,2-
b]pyridazin-6- yl)piperidin-1-yl)- N-methylacetamide Gen-5- as
A2-B2- E2-E6- C2-D1- E5b-E8 546 547 (M + H) 212 ##STR00548##
2-((2-ethyl-6-(1-(2-(3- hydroxyazetidin-1-yl)-2-
oxoethyl)piperidin-4-yl) imidazo[1,2-b]pyridazin-
3-yl)(methyl)amino)-4- (4-fluorophenyl)thiazole- 5-carbonitrile
Gen-5- ah A2-B2- C1-D2- E2-E6- E5b-E8 574 575 (M + H) 213
##STR00549## 2-(6-((2-ethyl-6-(1-(2-(3- hydroxyazetidin-1-yl)-2-
oxoethyl)piperidin-4-yl) imidazo[1,2-b]pyridazin-
3-yl)(methyl)amino) pyridin-2-yl)-5- fluorobenzonitrile Gen-5- aac
A2-B2- E2-E6- C2-D2- E5b-E8 568 569 (M + H) 214 ##STR00550##
2-(4-(2-ethyl-3-((6-(4- fluorophenyl)pyridin-2- yl)(methyl)amino)
imidazo[1,2-b]pyridazin- 6-yl)piperidin-1-yl)-1-(3-
hydroxyazetidin-1-yl) ethanone Gen-5- ay A2-B2- E2-E6- C2-D2-
E5b-E8 543 544 (M + H) 215 ##STR00551## 2-(4-(2-ethyl-3-((4-(4-
fluorophenyl)pyrimidin- 2-yl)(methyl)amino)
imidazo[1,2-b]pyridazin- 6-yl)piperidin-1-yl)-1-(3-
hydroxyazetidin-1-yl) ethanone Gen-5- aaa A2-B2- E2-E6- C2-D2-
E5b-E8 544 545 (M + H) 216 ##STR00552## 2-(4-(2-ethyl-3-((2-(4-
fluorophenyl)pyrimidin- 4-yl)(methyl)amino)
imidazo[1,2-b]pyridazin- 6-yl)piperidin-1-yl)-1-
(3-hydroxyazetidin-1- yl)ethanone Gen-5- aae A2-B2- E2-E6- C2-D3-
E5b-E8
544 545 (M + H) 217 ##STR00553## 2-((2-ethyl-6-(1-(2-(3-
hydroxyazetidin-1-yl)-2- oxoethyl)piperidin-4-yl)
imidazo[1,2-b]pyridazin- 3-yl)(methyl)amino)-6- (4-fluorophenyl)
nicotinonitrile Gen-5- aw A2-B2- E2-E6- C2-D3- E5b-E8 568 569 (M +
H) 218 ##STR00554## 6-((2-ethyl-6-(1-(2-(3-
hydroxyazetidin-1-yl)-2- oxoethyl)piperidin-4-yl)
imidazo[1,2-b]pyridazin- 3-yl)(methyl)amino)-2- (4-fluorophenyl)
nicotinonitrile Gen-5- au A2-B2- E2-E6- C2-D3- E5b-E8 568 569 (M +
H) 219 ##STR00555## 2-(5-((2-ethyl-6- (piperidin-4-yl)
imidazo[1,2-b]pyridazin- 3-yl)(methyl)amino)-
1,2,4-thiadiazol-3-yl)-5- fluorobenzonitrile Gen-5- ao A2-B2-
E2-E6- C2-See Cpd 219 462 463 (M + H) 220 ##STR00556##
2-(5-((2-ethyl-6-(1-(2-(3- hydroxyazetidin-1-yl)-2-
oxoethyl)piperidin-4-yl) imidazo[1,2-b]pyridazin-
3-yl)(methyl)amino)- 1,2,4-thiadiazol-3-yl)-5- fluorobenzonitrile
Cpd 219 A2-B2- E2-E6- C2-See Cpd 219- E5b-E8 575 576 (M + H)
TABLE-US-00004 TABLE III NMR data of illustrative compounds of the
invention. Cpd NMR data (.delta.) 2 .sup.1H NMR (300 MHz,
CDCl.sub.3-d) .delta. ppm 8.84 (1 H, d), 8.21-8.11 (2 H, m), 7.19
(2 H, t), 6.92 (1 H, d), 4.69 (1 H, br. s), 4.51-4.42 (1 H, m),
4.30 (1 H, dd), 4.18-4.10 (1 H, m), 3.92 (1 H, dd), 3.63 (3 H, s),
3.45 (4 H, br. s), 3.26-3.09 (2 H, m), 2.86-2.72 (6 H, m), 1.36 (3
H, t) 23 .sup.1H NMR (300 MHz, CDCl.sub.3-d) .delta. ppm 9.05 (1 H,
d), 8.20-8.08 (2 H, m), 7.59 (1 H, d), 7.18 (2 H, t), 4.73-4.60 (1
H, m), 4.53-4.41 (1 H, m), 4.32-4.16 (2 H, m), 4.03- 3.90 (1 H, m),
3.65 (3 H, s), 3.50-3.20 (4 H, m), 2.91-2.60 (3 H, m), 2.75-2.62 (2
H, m), 2.18-2.00 (4 H, m), 1.38 (3 H, t) 24 .sup.1H NMR (300 MHz,
CDCl.sub.3-d) .delta. ppm 9.05 (1 H, s), 8.14 (2 H, dd), 7.61 (1 H,
br. s), 7.23-7.12 (2 H, m), 4.52 (1 H, dd), 3.79-3.56 (7 H, m),
3.56-3.42 (2 H, m), 3.42- 3.25 (2 H, m), 2.91-2.74 (6 H, m),
2.20-2.01 (4 H, m), 2.02-1.89 (1 H, m), 1.38 (3 H, t) 25 .sup.1H
NMR (300 MHz, CDCl.sub.3-d) .delta. ppm 9.04 (1 H, s), 8.19-8.07 (2
H, m), 7.58 (1 H, br. s), 7.17 (2 H, t), 4.60-4.44 (1 H, m),
3.78-3.56 (6 H, m), 3.54-3.26 (3 H, m), 3.25- 3.12 (2 H, m),
2.89-2.70 (3 H, m), 2.66-2.35 (3 H, m), 2.15-1.88 (5 H, m), 1.38 (3
H, t) 27 .sup.1H NMR (400 MHz, CDCl.sub.3-d) .delta. ppm 8.16 (2 H,
dd), 7.70 (1 H, d), 7.17 (2 H, t), 6.89 (1 H, d), 4.73-4.62 (1 H,
m), 4.48-4.39 (1 H, m), 4.33-4.23 (1 H, m), 4.08 (1 H, dd), 3.89 (1
H, dd), 3.61 (3 H, s), 3.49 (4 H, br. s), 3.07 (2 H, s), 2.74 (2 H,
q), 2.61 (4 H, br. s), 1.35 (3 H, t) 30 .sup.1H NMR (400 MHz,
CDCl.sub.3-d) .delta. ppm 7.89-7.81 (2 H, m), 7.70 (1 H, d), 7.08
(2 H, t), 7.05-7.01 (1 H, m), 6.83 (1 H, d), 6.64 (1 H, s), 3.61 (3
H, s), 3.50-3.42 (4 H, m), 3.04 (2 H, s), 2.84 (3 H, d), 2.76 (2 H,
q), 2.65-2.57 (4 H, m), 1.34 (3 H, t) 40 .sup.1H NMR (400 MHz,
CDCl.sub.3-d) .delta. ppm 7.89-7.82 (2 H, m), 7.69 (1 H, d), 7.08
(2 H, t), 6.82 (1 H, d), 6.64 (1 H, s), 5.55 (1 H, br. s),
4.83-4.73 (1 H, m), 3.66 (1 H, t), 3.60 (3 H, s), 3.50-3.41 (4 H,
m), 3.40-3.34 (1 H, m), 2.75 (2 H, q), 2.71-2.65 (4 H, m),
2.64-2.57 (2 H, m), 1.34 (3 H, t) 43 .sup.1H NMR (400 MHz,
CDCl.sub.3-d) .delta. ppm 7.80-7.73 (2 H, m), 7.61 (1 H, d), 7.10
(2 H, t), 6.80 (1 H, d), 4.68-4.59 (2 H, m), 3.52 (3 H, s),
3.51-3.43 (4 H, m), 3.22-3.13 (2 H, m), 3.06 (3 H, s), 2.93 (3 H,
s), 2.67 (2 H, q), 2.61-2.51 (4 H, m), 1.28 (3 H, t) 45 .sup.1H NMR
(400 MHz, MeOD-d.sub.4) .delta. ppm 7.79-7.68 (2 H, m), 7.61 (1 H,
dd), 7.25 (1 H, d), 7.22-7.13 (1 H, m), 7.07 (1 H, t), 3.64-3.48 (7
H, m) 3.26 (2 H, d), 3.08 (3 H, d), 2.93 (3 H, d), 2.80-2.69 (2 H,
m), 2.58-2.65 (4 H, m), 1.33 (3 H, td) 63 .sup.1H NMR (400 MHz,
CDCl.sub.3-d) .delta. ppm 7.89-7.82 (2 H, m), 7.71 (1 H, d), 7.09
(2 H, t), 6.80 (1 H, d), 6.66 (1 H, s), 4.15-4.00 (2 H, m),
4.00-3.92 (1 H, m), 3.88-3.77 (2 H, m), 3.60 (4 H, s), 3.38-3.26 (2
H, m), 3.26-2.99 (3 H, m), 2.76 (2 H, q), 2.54-2.42 (1 H, m),
2.41-2.32 (1 H, m), 2.24 (6 H, s), 2.05-1.91 (2 H, m), 1.34 (3 H,
t) 67 .sup.1H NMR (400 MHz, CDCl.sub.3-d) .delta. ppm 7.89-7.81 (2
H, m), 7.72 (1 H, d), 7.08 (2 H, t), 6.82 (1 H, d), 6.66 (1 H, s),
4.23-4.09 (1 H, m), 4.09-4.01 (1 H, m), 3.96 (1 H, br. d),
3.84-3.63 (3 H, m), 3.60 (3 H, s), 3.32-3.08 (3 H, m), 2.94 (3 H,
s), 2.76 (2 H, q), 1.34 (3 H, t) 119 .sup.1H NMR (400 MHz,
MeOD-d.sub.4) .delta. ppm 7.91-7.83 (2 H, m), 7.70 (1 H, d), 7.10
(2 H, t), 6.92-6.87 (2 H, m), 3.81 (1 H, d), 3.75-3.66 (2 H, m),
3.64-3.53 (6 H, m), 2.84 (3 H, s), 2.70 (2 H, q), 2.44-2.31 (1 H,
m), 2.28-2.14 (1 H, m), 1.31 (3 H, t) 143 .sup.1H NMR (400 MHz,
CDCl.sub.3-d) .delta. ppm 7.86 (2 H, dd), 7.65 (1 H, d), 7.08 (2 H,
t), 6.63 (1 H, s), 6.60 (1 H, d), 3.73-3.64 (2 H, m), 3.62 (3 H,
s), 3.61-3.57 (1 H, m), 3.57- 3.50 (1 H, m), 3.47-3.39 (1 H, m),
3.24 (1 H, dd), 2.75 (2 H, q), 2.61-2.49 (1 H, m), 2.18-2.08 (1 H,
m), 1.88-1.77 (1 H, m), 1.34 (3 H, t) 147 .sup.1H NMR (400 MHz,
CDCl.sub.3-d) .delta. ppm 7.91-7.80 (2 H, m), 7.64 (1 H, d), 7.07
(2 H, t), 6.63 (1 H, s), 6.57 (1 H, d), 3.76-3.63 (5 H, m),
3.62-3.57 (4 H, m), 3.45-3.35 (1 H, m), 3.23 (1 H, dd), 2.98-2.87
(1 H, m), 2.74 (2 H, q), 2.58-2.46 (4 H, m), 2.25-2.15 (1 H, m),
1.96-1.84 (1 H, m), 1.33 (3 H, t) 161 .sup.1H NMR (400 MHz,
CDCl.sub.3-d) .delta. ppm 8.24-8.08 (2 H, m), 7.76 (1 H, d), 7.18
(2 H, t), 6.89 (1 H, d), 4.22-4.06 (2 H, m), 4.03-3.93 (1 H, m),
3.92-3.65 (3 H, m), 3.63 (3 H, s), 3.36-3.08 (3 H, m), 2.98 (3 H,
s), 2.76 (2 H, q), 2.32-2.13 (1 H, m), 1.36 (3 H, t) 172 .sup.1H
NMR (400 MHz, CDCl.sub.3-d) .delta. ppm 8.20-8.12 (2 H, m), 7.80 (1
H, d), 7.17 (2 H, t), 6.73 (1 H, d), 3.94-3.84 (4 H, m), 3.64 (3 H,
s), 2.82-2.72 (4 H, m), 1.37 (3 H, t) 189 .sup.1H NMR (300 MHz,
CDCl.sub.3-d) .delta. ppm 8.21-8.11 (2 H, m), 7.69 (1 H, d), 7.17
(2 H, t), 6.47 (1 H, d), 4.73-4.63 (1 H, m), 4.36-4.15 (4 H, m),
4.00 (1 H, dd), 3.94-3.78 (4 H, m), 3.61 (3 H, s), 3.28 (2 H, d),
2.74 (2 H, q), 1.35 (3 H, t) 190 .sup.1H NMR (400 MHz,
CDCl.sub.3-d) .delta. ppm 8.20-8.11 (2 H, m), 7.84 (1 H, d), 7.17
(2 H, t), 6.53 (1 H, d), 5.11 (1 H, br. d), 4.51-4.35 (3 H, m),
3.98 (2 H, dd), 3.61 (3 H, s), 3.00 (3 H, s), 2.84-2.71 (2 H, m),
1.38 (3 H, t) 198 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.16 (1 H, d), 7.95-7.89 (2 H, m), 7.42 (1 H, d), 7.24 (3 H, t),
3.61-3.48 (5 H, m), 3.06-2.77 (10 H, m), 2.05-1.95 (2 H, m), 1.83-
1.69 (2 H, m) 213 .sup.1H NMR (300 MHz, CDCl.sub.3-d) .delta. ppm
7.90 (1 H, dd), 7.83 (1 H, d), 7.53 (1 H, dd), 7.48- 7.35 (2 H, m),
7.11 (1 H, d), 6.97 (1 H, d), 6.13 (1 H, d), 4.69-4.61 (1 H, m),
4.50- 4.41 (1 H, m), 4.26 (1 H, dd), 4.13 (1 H, dd), 3.91 (1 H,
dd), 3.63 (3 H, s), 3.05 (2 H, d), 3.02-2.89 (2 H, m), 2.81-2.58 (3
H, m), 2.26-2.13 (2 H, m), 1.96-1.80 (4 H, m), 1.32 (3 H, t) 214
.sup.1H NMR (400 MHz, CDCl.sub.3-d) .delta. ppm 8.12-8.02 (2 H, m),
7.82 (1 H, d), 7.39 (1 H, t), 7.20-7.08 (3 H, m), 6.96 (1 H, d),
6.06 (1 H, d), 4.70-4.59 (1 H, m), 4.47-4.38 (1 H, m), 4.32-4.19 (1
H, m), 4.07 (1 H, dd), 3.88 (1 H, dd), 3.60 (3 H, s), 3.01 (2 H,
s), 2.99-2.92 (2 H, m), 2.78-2.66 (3 H, m), 2.26-2.10 (2 H, m),
1.92-1.81 (4 H, m), 1.30 (3 H, t) 215 .sup.1H NMR (400 MHz,
CDCl.sub.3-d) .delta. ppm 8.50-7.40 (4 H, m), 7.24-6.87 (4 H, m),
4.71- 4.54 (1 H, m), 4.46-4.34 (1 H, m), 4.23 (1 H, dd), 4.06 (1 H,
dd), 4.02-3.92 (1 H, m), 3.87 (1 H, dd), 3.61 (3 H, s), 3.07-2.88
(4 H, m), 2.85-2.61 (3 H, m), 2.24-2.06 (2 H, m), 1.90-1.74 (4 H,
m), 1.31 (3 H, t) 218 .sup.1H NMR (400 MHz, CDCl.sub.3-d) .delta.
ppm 8.07 (2 H, br. s.), 7.85 (1 H, d), 7.60 (1 H, d), 7.21 (2 H,
t), 7.02 (1 H, d), 6.16-6.03 (1 H, m), 4.68-4.61 (1 H, m),
4.45-4.37 (1 H, m), 4.31-4.23 (1 H, m), 4.07 (1 H, dd), 3.88 (1 H,
dd), 3.60 (3 H, s), 3.06-2.93 (4 H, m), 2.83-2.67 (5 H, m),
2.25-2.12 (2 H, m), 1.91-1.81 (2 H, m), 1.32 (3 H, t) 220 .sup.1H
NMR (400 MHz, CDCl.sub.3-d) .delta. ppm 8.35 (1 H, dd), 7.88 (1 H,
d), 7.51 (1 H, dd), 7.42- 7.35 (1 H, m), 7.10 (1 H, d), 4.67-4.60
(1 H, m), 4.50-4.38 (1 H, m), 4.32-4.23 (1 H, m), 4.19-4.10 (1 H,
m), 3.92 (1 H, dd), 3.73 (3 H, s), 3.29-3.12 (4 H, m), 2.93- 2.85
(1 H, m), 2.82 (2 H, q), 2.64-2.46 (2 H, br. m), 2.12-1.95 (4 H,
br. m), 1.38 (3 H, t)
BIOLOGICAL EXAMPLES
EXAMPLE 3
In Vitro Assays
3.1. Principle
[1230] The principle of the assay consists in quantifying the
released choline with an enzymatic method using choline oxidase and
peroxidase. Choline oxydation by choline oxydase releases betaine
and peroxide. The latter is quantified in presence of HRP that
converts the peroxide detection agent TOOS and 4-aminoantipyrine
into quinoneimine dye. The appearance of quinoneimine dye is
measured spectrophotometrically at 555 nm and is proportional to
the amount of choline released by ENPP2. Inhibition of ENPP2 will
result in a decrease of the signal.
3.2. Human ENPP2 (hENPP2) Assay
3.2.1. LPC as Substrate
[1231] Compound IC.sub.50 values are determined in a hENPP2
(UniProtKB/SwissProt Sequence ref Q13822) biochemical assay using
LPC as substrate.
[1232] 5 .mu.L of a dilution series of compound, starting from 20
.mu.M highest concentration, 1/5 dilution, is added to the wells.
hENPP2 is used at a final concentration of 1 .mu.g/mL or 3 .mu.g/mL
(it will be appreciated by the skilled person that the potency read
out is independent of the enzyme concentration). The enzyme is
diluted in 50 mM Tris-HCl pH 8.5, 500 mM NaCl, 5 mM KCl, 10 mM
CaCl.sub.2, 0.1% fatty acid free BSA in a total volume of 10 .mu.L.
the reaction is started by the addition of 10 .mu.L of 150 .mu.M
LPC (palmitoyl 16:0) diluted in the same buffer as described above
and the mixture is incubated at 37.degree. C. for 30 min. The
reaction is terminated and choline quantified by the addition of a
25 .mu.L of a mixture containing 0.6 U/mL of choline oxidase, 0.6
U/mL of peroxydase, 1.8 mM TOOS, 1.2 mM amino-antipyrine, 20 mM
EGTA (stop-developer solution) diluted in the buffer described
above. Luminescence is read on the Envision after an incubation of
30 min at room temperature (Excitation 555 nm, excitation
light=70%).
TABLE-US-00005 TABLE IV LPC hENPP2 assay IC.sub.50 of the compounds
of the invention. Cpd # LPC - IC.sub.50 1 * 2 *** 3 * 4 *** 5 *** 6
*** 7 *** 8 *** 9 ** 10 *** 11 *** 12 * 13 * 14 * 15 * 16 * 15 * 18
* 19 * 20 * 21 *** 22 * 23 *** 24 *** 25 *** 26 *** 27 **** 28 ***
29 *** 30 ** 31 *** 32 * 33 *** 34 *** 35 * 36 *** 37 *** 38 * 39 *
40 *** 41 ** 42 *** 43 *** 44 **** 45 **** 46 *** 47 * 48 *** 49 **
50 * 51 * 52 ** 53 * 54 * 55 *** 56 * 57 *** 58 * 59 * 60 * 61 * 62
* 63 **** 64 *** 65 *** 66 * 67 *** 68 *** 69 * 70 ** 71 * 72 ** 73
*** 74 * 75 * 76 * 77 * 78 * 79 * 80 * 81 * 82 * 83 * 84 *** 85 *
86 * 87 * 88 ** 89 ** 90 * 91 * 92 * 93 * 94 * 95 * 96 * 97 ** 98 *
99 * 100 * 101 * 102 * 103 * 104 * 105 * 106 * 107 ** 108 ** 109 **
110 * 111 * 112 * 113 * 114 * 115 * 116 * 117 * 118 ** 119 *** 120
*** 121 * 122 * 123 * 124 * 125 * 126 ** 127 * 128 * 129 * 130 *
131 * 132 * 133 * 134 * 135 ** 136 * 137 * 138 * 139 * 140 * 141 *
142 * 143 * 144 ** 145 ** 146 ** 147 *** 148 ** 149 **** 150 * 151
* 152 ** 153 * 154 * 155 *** 156 ** 157 ** 158 ** 159 * 160 ****
161 *** 162 *** 163 * 164 *** 165 *** 166 *** 167 **** 168 **** 169
**** 170 *** 171 *** 172 *** 173 *** 174 **** 175 **** 176 **** 177
**** 178 ** 179 **** 180 **** 181 **** 182 **** 183 **** 184 ****
185 * 186 *** 187 *** 188 **** 189 **** 190 **** 191 *** 192 ***
194 * 195 * 196 * 197 ** 198 *** 199 * 200 * 201 *** 202 ** 203 **
204 *** 205 *** 206 ** 207 *** 208 *** 209 *** 210 * 211 * 212 ****
213 **** 214 ** 215 *** 216 ** 217 * 218 *** 219 * 220 *** ****:
0.01-100 nM ***: >100-500 nM **: >500-1000 nM *: >1000
nM
3.2.2. FS-3 as Substrate
[1233] Compound IC.sub.50 values are determined in a fluorescent
hENPP2 (UniProtKB/SwissProt Sequence ref Q13822) biochemical assay
using the fluorogenic autotaxin substrate FS-3 as substrate. FS-3
is a doubly labeled analog of LPC wherein the fluorophore is
quenched through intramolecular energy transfer. Without hENPP2,
the emission of the probe is quenched. If the substrate is
hydrolyzed by hENPP2, the emission of the probe is not quenched
anymore resulting in a fluorescence increase. Inhibition of hENPP2
by compounds will result in a decrease of the signal.
[1234] 10 .mu.L of a dilution series of compound, starting from 20
.mu.M highest concentration, 1/5 dilution, is added to the wells.
hENPP2 is used at a final concentration of 0.4 .mu.g/mL or 0.64
.mu.g/mL (it will be appreciated by the skilled person that the
potency read out is independent of the enzyme concentration). The
enzyme is diluted in 50 mM Tris-HCl pH 8.0, 250 mM NaCl, 5 mM KCl,
1 mM MgCl.sub.2, 1 mM CaCl.sub.2, 0.1% fatty acid free BSA in a
total volume of 20 .mu.L. Enzyme mixture is added to compounds and
the resulting mixture is incubated for 30 min at room temperature
under shaking. The reaction is started by the addition of 20 .mu.L
of 0.75 .mu.M FS-3 diluted in the same buffer as described above
and the mixture is incubated at 30.degree. C. for 30 min.
Fluorescence is read on the Envision (Excitation 485 nm, emission
520 nM).
TABLE-US-00006 TABLE V FS3 hENPP2 assay IC.sub.50 of the compounds
of the invention. Cpd # FS3 - IC.sub.50 4 **** 5 **** 6 **** 7 ****
8 **** 9 **** 10 **** 11 **** 12 **** 16 ** 19 * 21 **** 22 *** 23
**** 24 **** 25 **** 26 **** 27 **** 29 **** 33 **** 34 **** 40
**** 42 **** 43 **** 45 **** 46 **** 47 **** 48 **** 49 **** 51
**** 52 **** 53 **** 54 **** 55 **** 57 **** 60 **** 61 **** 63
**** 64 **** 65 **** 67 **** 71 **** 72 **** 78 **** 79 *** 81 ****
82 **** 83 **** 91 *** 93 **** 94 **** 95 **** 96 **** 97 **** 98
**** 99 **** 100 **** 101 *** 102 **** 108 **** 109 **** 114 ** 115
**** 116 **** 122 **** 123 **** 124 **** 125 **** 126 **** 127 ****
129 **** 131 **** 133 **** 134 **** 137 **** 142 **** 143 **** 145
**** 147 **** 150 **** 151 **** 152 **** 154 **** 171 **** 172 ****
193 **** 194 **** 195 **** 196 **** 197 **** 198 **** 199 **** 200
**** 201 **** 202 **** 212 **** 213 **** 214 **** 215 **** 216 ****
217 ** 218 **** ****: 0.01-25 nM ***: >25-50 nM **: >50-100
nM *: >100 nM
3.3. Mouse ENPP2 (mENPP2)
3.3.1. LPC as Substrate
[1235] Compound IC.sub.50 values are determined in a mENPP2
(UniProtKB/SwissProt Sequence ref Q9R1E6) biochemical assay using
LPC as substrate.
[1236] Five .mu.L of a dilution series of compound, starting from
20 .mu.M highest concentration, 1/5 dilution, is added to the
wells. mENPP2 is used at a final concentration of 1 .mu.g/mL. The
enzyme is diluted in 50 mM Tris-HCl pH 8.5, 500 mM NaCl, 5 mM KCl,
10 mM CaCl.sub.2, 0.1% fatty acid free BSA in a total volume of 10
.mu.L. the reaction is started by the addition of 10 .mu.L of 150
.mu.M LPC (palmitoyl 16:0) diluted in the same buffer as described
above and the mixture is incubated at 37.degree. C. for 30 min. The
reaction is terminated and choline quantified by the addition of a
25 .mu.L of a mixture containing 0.6 U/mL of choline oxidase, 0.6
U/mL of peroxydase, 1.8 mM TOOS, 1.2 mM amino-antipyrine, 20 mM
EGTA (stop-developer solution) diluted in the buffer described
above. Luminescence is read on the Envision after an incubation of
30 min at room temperature (Excitation 555 nm, excitation
light=70%).
3.3.2. FS-3 as Substrate
[1237] Compound IC.sub.50 values are determined in a fluorescent
mENPP2 (UniProtKB/SwissProt Sequence ref Q9R1E6) biochemical assay
using the fluorogenic autotaxin substrate FS-3 as substrate. FS-3
is a doubly labeled analog of LPC wherein the fluorophore is
quenched through intramolecular energy transfer. Without mENPP2,
the emission of the probe is quenched. If the substrate is
hydrolyzed by mENPP2, the emission of the probe is not quenched
anymore resulting in a fluorescence increase. Inhibition of mENPP2
by compounds will result in a decrease of the signal.
[1238] Ten .mu.L of a dilution series of compound, starting from 20
.mu.M highest concentration, 1/5 dilution, is added to the wells.
mENPP2 is used at a final concentration of 0.4 .mu.g/mL. The enzyme
is diluted in 50 mM Tris-HCl pH 8.0, 250 mM NaCl, 5 mM KCl, 1 mM
MgCl.sub.2, 1 mM CaCl.sub.2, 0.1% fatty acid free BSA in a total
volume of 20 .mu.L. Enzyme mixture is added to compounds and the
resulting mixture is incubated for 30 min at room temperature under
shaking. The reaction is started by the addition of 20 .mu.L of
0.75 .mu.M FS-3 diluted in the same buffer as described above and
the mixture is incubated at 30.degree. C. for 30 min. Fluorescence
is read on the Envision (Excitation 485 nm, emission 520 nM).
EXAMPLE 4
Whole Blood Assay
4.1. Human LPA Assay
[1239] Blood is collected from healthy volunteers who gave informed
consent into sodium heparin tubes by venipuncture, then gently
inverted several times to prevent clotting. Tubes are centrifuged
at 3000 rpm for 15 min at 4.degree. C. then plasma is stored at
-80.degree. C. Compounds are diluted in DMSO in concentration
dependent manner then 0.5 .mu.L are dispensed into 96-wells plate
placed in ice. Plasma is defrosted on ice then 49.5 .mu.L of plasma
are added into the well containing 0.5 .mu.L of compound (1% DMSO
final). Plates are covered with a lid in polypropylene and
incubated at +37.degree. C., 5% CO.sub.2, for 2 h under gentle
shaking (except controls which are stored at -20.degree. C.).
[1240] At the end of the incubation, controls are defrosted in ice
and transferred in the incubated plates for LC-MS/MS analysis with
a non GLP-validated method. For the analysis, plasma proteins from
a 10 .mu.L incubated plates are precipitated with an excess of
methanol containing the internal standard, LPA 17:0. After
centrifugation, the corresponding supernatant is injected on a C18
column. Analytes are eluted out of the column under isocratic
conditions. An API5500 QTRAP mass spectrometer (ABSciex.TM.) is
used for the detection of LPA 18:2. No calibration curve is
prepared for LPA 18:2, however relative quantities are evaluated
based on the peak area.
4.2. Rat or Mouse LPA Assay
[1241] Whole blood is collected from rats or mouse by
exsanguinations on sodium heparin tube, then after centrifugation
at 3000 rpm for 15 min at 4.degree. C., plasma is stored at
-80.degree. C. Compounds are diluted in DMSO in concentration
dependent manner then 0.5 .mu.L are dispensed into 96-wells plate
placed in ice. Plasma is defrosted on ice then 49.5 .mu.L of plasma
are added into the well containing 0.5 .mu.L of compound (1% DMSO
final). Plates are covered with a lid in polypropylene and
incubated at +37.degree. C., 5% CO.sub.2, for 2 h under gentle
shaking (except controls which are stored at -20.degree. C.).
[1242] At the end of the incubation, controls are defrosted in ice
and transferred in the incubated plates for LC-MS/MS analysis with
a non GLP-validated method. For the analysis, plasma proteins from
a 10 .mu.L incubated plates are precipitated with an excess of
methanol containing the internal standard, LPA 17:0. After
centrifugation, the corresponding supernatant is injected on a C18
column. Analytes are eluted out of the column under isocratic
conditions. An API5500 QTRAP mass spectrometer (ABSciex.TM.) is
used for the detection of LPA 18:2. No calibration curve is
prepared for LPA 18:2, however relative quantities are evaluated
based on the peak area.
TABLE-US-00007 TABLE VI Rat/Mouse whole blood assay IC.sub.50 of
the compounds of the invention. Cpd # IC.sub.50 Species 2 * Rat 5 *
Rat 6 *** Rat 7 *** Rat 10 * Rat 12 * Rat 14 * Rat 16 * Rat 19 *
Rat 21 * Mouse 23 *** Rat 24 **** Rat 25 **** Rat 40 *** Rat 42 ***
Rat 63 **** Rat 118 * Rat 149 **** Rat 198 **** Rat 205 *** Rat 206
*** Rat 213 *** Rat 216 * Rat 218 *** Rat ****: 0.01-100 nM ***:
>100-500 nM **: >500-1000 nM *: >1000 nM
EXAMPLE 5
In Vivo Models
5.1. Tobacco Smoke (TS) Model
5.1.1. Lungs Inflammatory Cells Recruitment Evaluation
5.1.1.1. Overview
[1243] The aim of this experiment is to evaluate the efficacy and
potency of a test compound administered p.o., once or twice daily
on days 6 to 11, vs reference compounds, on pulmonary inflammation
induced by 11 days of TS-exposure in female C57BL/6J mice, by
assessing the effect of a test compound on the tobacco smoke
induced recruitment of inflammatory cells to the lungs.
5.1.1.2. Protocol
[1244] The test compounds are formulated in PEG200/0.5%
methylcellulose (25/75, v/v) and are given at a dose volume of 10
mL/kg. Roflumilast and Dexamethasone are included as positive and
negative control, respectively. Each treatment group consists of 10
mice.
[1245] A first group of mice is subjected to daily TS-exposure for
5 consecutive days and sacrificed on the day 6, 24 h after the
final TS-exposure.
[1246] A second group is exposed to air for 5 consecutive days
(sham exposure) and sacrificed on the day 6, 24 h after the final
air-exposure.
[1247] Compound and reference-treated groups are subjected to daily
TS-exposure for 11 consecutive days and sacrificed on the day 12,
24 h after the final TS-exposure. Mice are dosed p.o. on days 6 to
11, twice daily, 1 h prior to and 6 h after each TS-exposure, with
either vehicle, or the test compound at 3, 5, 10 or 30 mg/kg.
Another group is dosed p.o. on days 6 to 11, once daily, 1 h prior
to each TS-exposure, with either vehicle, or the test compound at a
selected dose, for example 10 mg/kg.
[1248] An additional group is dosed p.o., once daily, on days 6 to
11, with roflumilast at 5 mg/kg, 1 h prior to each TS-exposure.
Dexamethasone is dosed p.o., twice daily, on days 6 to 11, at 0.3
mg/kg, 1 h prior to and 6 h after each TS-exposure.
[1249] For each mouse, a BAL is performed using 0.4 mL of PBS. The
lavage fluid is centrifuged, the supernatant removed and the
resulting cell pellet re-suspended for total cell counts and
cytospin slide preparation. The remaining cells are re-pelleted and
frozen. The supernatants are stored at -40.degree. C. for possible
future analysis.
[1250] The lungs are dissected out and the left lobes are removed,
snap-frozen and stored at -80.degree. C. The right lobes are
inflated with 10% phosphate buffered formalin (PBF) to a pressure
of 18 cm PBF for 20 min and then immersed in PBF. After 24 h, the
right lobe samples are transferred to 70% ethanol and stored at
room temperature. Cell data are presented as individual data points
for each animal and the mean value calculated for each group.
[1251] Data are subjected to an unpaired Students "t" test. Data
from other groups are initially subjected to a one-way analysis of
variance test (ANOVA), followed by a Bonferroni correction for
multiple comparisons in order to test for differences between
treatment groups. A "p" value of <0.05 is considered to be
statistically significant.
[1252] Percentage inhibitions for the cell data are calculated
using the formula below:
% inhibition = ( 1 - ( treatment group result - sham group result
TS vehicule group result - sham group result ) * 100
##EQU00001##
5.1.1.3. Results
[1253] For example, when tested in this protocol, Compound 2 and 12
significantly inhibited the number of cells recovered in the BALF,
in particular macrophage cells, epithelial cells, and neutrophils
at 10 mg/kg twice daily p.o. (Compound 2 & 12) and 3 mg/kg
twice daily p.o. (Compound 2).
5.1.2. Compound Efficacy and Potency Evaluation
5.1.2.1. Overview
[1254] A second tobacco smoke (TS) experiment is carried out, aimed
at evaluating the efficacy and potency of a test compound
administered p.o., twice daily on days 6 to 11, vs a reference
compound, on pulmonary inflammation induced by 11 days of
TS-exposure, reading out the effects on gene expression in the
lungs. This second experiment consisted of 4 groups of mice.
5.1.2.2. Protocols
[1255] Three groups of mice are subjected to daily TS-exposure for
11 consecutive days and sacrificed on the day 12, 24 h after the
final TS-exposure. Two groups are dosed, p.o., on days 6 to 11,
twice daily (b.i.d.), 1 h prior to and 6 h after each TS-exposure,
with either vehicle or the test compound at 10 mg/kg. The third
group is dosed p.o., on days 6 to 11, once daily (q.d.) with
Roflumilast at 5 mg/kg, 1 h prior to each TS-exposure. This group
receives vehicle 6 h after each TS-exposure. One further group is
exposed to air for 11 consecutive days and receive vehicle 1 h
prior to and 6 h after exposure on days 6 to 11. This group is also
sacrificed on the day 12, 24 h after the final exposure.
[1256] All groups receive a final dose, of the relevant treatment,
2 h prior to sacrifice on day 12. One final group is exposed to air
for 11 consecutive days and received vehicle 1 h prior to and 6 h
after exposure on days 6 to 11. This group is also sacrificed on
the day 12, 24 h after the final exposure. Mice receive a dose
volume of 10 mL/kg. Each group consists in 10 subjects.
[1257] Mice are euthanized, by intra-peritoneal barbiturate
anaesthetic overdose, on day 12, 24 h after the final air or
TS-exposure. All mice receive a final dose of the relevant
treatment, 2 h prior to sacrifice. The lungs are dissected out and
placed in RNAse-free 15 mL tubes containing .about.5 mL of RNAlater
solution, ensuring the tissue is completely submerged. The lungs
are stored overnight at 4.degree. C. Following overnight
incubation, the lungs are removed from RNAlater, the left and right
lobes are separated, placed in individual tubes and stored at
-80.degree. C.
[1258] RNA extractions are performed for 5 mice per group using
Qiagen RNeasy Mini Kit according to the manufacturer's
specifications (Animal tissue protocol). Total RNA are then eluted
in RNase-free water (30 .mu.l for four reference samples and 50
.mu.L for the twenty-four test samples). Quality of the samples is
assessed by measurement of their concentration in RNA using a
NanoDrop ND-1000 spectrophotometer and by the measurement of RNA
integrity using an 2100 Bioanalyzer (Agilent Technologies).
[1259] RNA preparations are of good quality (RIN value lies between
7.6 and 9.2) and subjected to quantitative real-time PCR (QrtPCR),
which involved a first cDNA synthesis step. To this end, 300 ng of
total RNA are reverse transcribed using the High capacity cDNA
synthesis Kit (Applied Biosystems.TM.) with random hexamers.
Quantitative PCR reactions are performed using Quanti-Fast
SYBR.RTM. Green PCR Master Mix (Qiagen.TM.) and gene-specific
primer pairs for .beta.-actin (Eurogentech.TM.) and QuantiTect
primer assays for all other tested genes (Qiagen.TM.). For the
genes of interest, the following Quantitect primer pairs are used:
CCL2 (QT00167832); CDK1 (QT00167734); SAA3 QT00249823), TIMP1
(QT00996282); Slc26a4 (QT00131908); LCN2 (QT00113407); CXCL5
(QT01658146), MMP12 (QT00098945); PLA1a (QT00161448); TNFsF11
(QT00147385). Reactions are carried out with a denaturation step at
95.degree. C. for 5 min, followed by 40 cycles (95.degree. C. for
10 sec, 60.degree. C. for 1 min) in a ViiATM7 Real-Time PCR System
(Applied Biosystems.TM.).
[1260] Real-time PCR data for each target gene are expressed as
2.sup.-.DELTA..DELTA.Ct relative quantification versus endogenous
.beta.-actin. For statistical analysis, a 2-way analysis of
variance (ANOVA) followed by a Dunnett's post-hoc test versus the
TS-vehicle group is performed.
[1261] The relevance of CCL2, CDK1, SAA3, TIMP1, Slc26a4, LCN2,
CXCL5, MMP12, PLA1a, and TNFsF11 towards COPD is well-established
through literature data based on patient specimen. A reference
towards the relevant paper for each gene is provided in Table VII
below.
5.1.2.3. Results
[1262] The increase in relative expression levels caused by the
tobacco smoke treatment is measured, and increase in the expression
of this relevant gene set upon tobacco smoke treatment further
validates the relevance of the model applied. Roflumilast, an
approved treatment for COPD, is taken along as positive control in
the experiment.
[1263] The inhibition of ENPP2 in a therapeutic setting strongly
suppresses the increase in expression of disease-relevant genes in
lungs of tobacco smoke-treated mice, providing a strong support for
key a role of ENPP2 in the pathogenesis of COPD.
TABLE-US-00008 TABLE VII TS induced relative expression levels in
selected genes Gene Name Literature reference CCL2 (Llinas et al.
2011) SAA3 (Bozinovski et al. 2008) TIMP1 (Tilley et al. 2011)
SLC26A4 (Nakao et al. 2008) LCN2 (Eagan et al. 2010) MMP12 (Demedts
et al. 2006)
5.2. CIA Model
5.2.1. Materials
[1264] Completed Freund's adjuvant (CFA) and incomplete Freund's
adjuvant (IFA) are purchased from Difco. Bovine collagen type II
(CII), lipopolysaccharide (LPS), and Enbrel is obtained from
Chondrex (Isle d'Abeau, France); Sigma (P4252, L'Isle d'Abeau,
France), Whyett (25 mg injectable syringe, France) Acros Organics
(Palo Alto, Calif.), respectively. All other reagents used are of
reagent grade and all solvents are of analytical grade.
5.2.2. Animals
[1265] Dark Agouti rats (male, 7-8 weeks old) are obtained from
Harlan Laboratories (Maison-Alfort, France). Rats are kept on a 12
h light/dark cycle (0700-1900). Temperature is maintained at
22.degree. C., and food and water are provided ad libitum.
5.2.3. Collagen Induced Arthritis (CIA)
[1266] One day before the experiment, CII solution (2 mg/mL) is
prepared with 0.05 M acetic acid and stored at 4.degree. C. Just
before the immunization, equal volumes of adjuvant (IFA) and CII
are mixed by a homogenizer in a pre-cooled glass bottle in an ice
water bath. Extra adjuvant and prolonged homogenization may be
required if an emulsion is not formed. 0.2 mL of the emulsion is
injected intradermally at the base of the tail of each rat on day
1, a second booster intradermal injection (CII solution at 2 mg/mL
in CFA 0.1 mL saline) is performed on day 9. This immunization
method is modified from published methods (Sims et al. 2004; Jou et
al. 2005).
5.2.4. Study Design
[1267] The therapeutic effects of the compounds are tested in the
rat CIA model. Rats are randomly divided into equal groups and each
group contains 10 rats. All rats are immunized on day 1 and boosted
on day 9. Therapeutic dosing lasted from day 16 to day 30. The
negative control group is treated with vehicle and the positive
control group with Enbrel (10 mg/kg, 3.times. week. s.c.). A
compound of interest is typically tested at 4 doses, e.g. 0.3, 1,
3, and 10 mg/kg, p.o.
5.2.5. Clinical Assessment of Arthritis
[1268] Arthritis is scored according to literature-described method
(Khachigian 2006; H.-S. Lin et al. 2007; Nishida et al. 2004, 20).
The swelling of each of the four paws is ranked with the arthritic
score as follows: 0--no symptoms; 1--mild, but definite redness and
swelling of one type of joint such as the ankle or wrist, or
apparent redness and swelling limited to individual digits,
regardless of the number of affected digits; 2--moderate redness
and swelling of two or more types of joints; 3--severe redness and
swelling of the entire paw including digits; 4--maximally inflamed
limb with involvement of multiple joints (maximum cumulative
clinical arthritis score 16 per animal) (Nishida et al. 2004).
[1269] To permit the meta-analysis of multiple studies the clinical
score values are normalised as follows:
[1270] AUC of clinical score (AUC score): The area under the curve
(AUC) from day 1 to day 14 is calculated for each individual rat.
The AUC of each animal is divided by the average AUC obtained for
the vehicle in the study from which the data on that animal is
obtained and multiplied by 100 (i.e. the AUC is expressed as a
percentage of the average vehicle AUC per study).
[1271] Clinical score increase from day 1 to day 14 (End point
score): The clinical score difference for each animal is divided by
the average clinical score difference obtained for the vehicle in
the study from which the data on that animal is obtained and
multiplied by 100 (i.e. the difference is expressed as a percentage
of the average clinical score difference for the vehicle per
study).
5.2.6. Change in Body Weight (%) After Onset of Arthritis
[1272] Clinically, body weight loss is associated with arthritis
(Shelton et al. 2005; Rall and Roubenoff 2004; Walsmith et al.
2004). Hence, changes in body weight after onset of arthritis can
be used as a non-specific endpoint to evaluate the effect of
therapeutics in the rat model. The change in body weight (%) after
onset of arthritis is calculated as follows:
Mice : Body Weight ( week 6 ) - Body Weight ( Week 5 ) Body Weight
( Week 5 ) * 100 % ##EQU00002## R ats : Body Weight ( week 4 ) -
Body Weight ( Week 3 ) Body Weight ( Week 3 ) * 100 %
##EQU00002.2##
5.2.7. Radiology
[1273] X-ray photos are taken of the hind paws of each individual
animal. A random blind identity number is assigned to each of the
photos, and the severity of bone erosion is ranked by two
independent scorers with the radiological Larsen's score system as
follows: 0--normal with intact bony outlines and normal joint
space; 1--slight abnormality with any one or two of the exterior
metatarsal bones showing slight bone erosion; 2--definite early
abnormality with any three to five of the exterior metatarsal bones
showing bone erosion; 3--medium destructive abnormality with all
the exterior metatarsal bones as well as any one or two of the
interior metatarsal bones showing definite bone erosions; 4--severe
destructive abnormality with all the metatarsal bones showing
definite bone erosion and at least one of the inner metatarsal
joints completely eroded leaving some bony joint outlines partly
preserved; 5--mutilating abnormality without bony outlines. This
scoring system is a modification from literature protocols
(Salvemini et al. 2001; Bush et al. 2002; Sims et al. 2004; Jou et
al. 2005).
5.2.8. Histology
[1274] After radiological analysis, the hind paws of mice are fixed
in 10% phosphate-buffered formalin (pH 7.4), decalcified with rapid
bone decalcifiant for fine histology (Laboratories Eurobio) and
embedded in paraffin. To ensure extensive evaluation of the
arthritic joints, at least four serial sections (5 .mu.m thick) are
cut and each series of sections are 100 .mu.m in between. The
sections are stained with hematoxylin and eosin (H&E).
Histologic examinations for synovial inflammation and bone and
cartilage damage are performed double blind. In each paw, four
parameters are assessed using a four-point scale. The parameters
are cell infiltration, pannus severity, cartilage erosion and bone
erosion. Scoring is performed according as follows: 1--normal,
2--mild, 3--moderate, 4--marked. These four scores are summed
together and represented as an additional score, namely the `RA
total score`.
5.2.9. Micro-Computed Tomography (.mu.CT) Analysis of Calcaneus
(Heel Bone)
[1275] Bone degradation observed in RA occurs especially at the
cortical bone and can be revealed by .mu.CT analysis (Sims et al.
2004; Oste et al. 2007). After scanning and 3D volume
reconstruction of the calcaneus bone, bone degradation is measured
as the number of discrete objects present per slide, isolated in
silico perpendicular to the longitudinal axis of the bone. The more
the bone is degraded, the more discrete objects are measured. 1000
slices, evenly distributed along the calcaneus (spaced by about
10.8 .mu.m), are analyzed.
5.2.10. Steady State PK
[1276] At day 7 or later, blood samples are collected at the
retro-orbital sinus with lithium heparin as anti-coagulant at the
following time points: predose, 1, 3 and 6 h. Whole blood samples
are centrifuged and the resulting plasma samples are stored at
-20.degree. C. pending analysis. Plasma concentrations of each test
compound are determined by an LC-MS/MS method in which the mass
spectrometer is operated in positive electrospray mode.
Pharmacokinetic parameters are calculated using Winnonlin.RTM.
(Pharsight.RTM., United States) and it is assumed that the predose
plasma levels are equal to the 24 h plasma levels.
5.3. Idiopathic Pulmonary Fibrosis Assay
5.3.1. Overview
[1277] The mouse bleomycin-induced fibrosis model mimics the main
characteristics of human lung fibrosis and is used to test
potential new therapies for lung fibrosis (Walters and Kleeberger
2001).
5.3.2. Protocol
[1278] In vivo efficacy of a compound of the invention is assessed
in a 10-days mouse preventive bleomycin-induced pulmonary fibrosis
model by oral route. Mice (20-25 g female C57BL/6; n=10-15 per
group) are treated with bleomycin sulfate (1.5 U/kg) via
intratracheal instillation at day 0 under isoflurane anesthesia,
and then treated with the compounds accordingly to the study
protocol from day 1 to day 10. Mice are kept on a 12 hr light/dark
cycle (07:00-19:00). The temperature is maintained at 22.degree.
C., and food and water are provided ad libitum. At sacrifice,
broncho alveolar lavage fluid (BALF; 2.times.0.75 mL PBS) is
collected from lungs.
[1279] This material is used to determine: [1280] the amount of
infiltrated inflammatory cells: [1281] All the BALF cells (for
example macrophage, eosinophil, neutrophil and epithelial cells)
are pelleted, resuspended in PBS and counted [1282] the total
amount of proteins using a Bradford dosing: [1283] this readout
reflects the vascular leakage occurring, leading to the formation
of an exudates in the lungs [1284] the amount of collagen using a
Sircol.TM. dosing (Available from Biocolor Ltd., 8 Meadowbank Road,
Carrickfergus, BT38 8YF, County Antrim, UK) [1285] This readout
reflects the level of extra-cellular matrix degradation and tissue
remodeling occurring in the lungs.
[1286] One lung of each mouse is also collected and prepared for
histological analysis using 10% neutral buffered formalin.
5.4. Septic Shock Model
[1287] Injection of lipopolysaccharide (LPS) induces a rapid
release of soluble tumour necrosis factor (TNF-alpha) into the
periphery. This model is used to analyse prospective blockers of
TNF release in vivo.
[1288] Six BALB/cJ female mice (20 g) per group are treated at the
intended dosing once, po. Thirty min later, LPS (15 .mu.g/kg; E.
Coli serotype 0111:B4) is injected ip. Ninety min later, mice are
euthanized and blood is collected. Circulating TNF alpha levels are
determined using commercially available ELISA kits. Dexamethasone
(5 .mu.g/kg) is used as a reference anti-inflammatory compound.
5.5. MAB Model
[1289] The MAB model allows a rapid assessment of the modulation of
an RA-like inflammatory response by therapeutics (Khachigian 2006).
DBA/J mice are injected i.v. with a cocktail of mAbs directed
against collagen II. One day later, compound treatment is
initiated. Three days later, mice receive an i.p. LPS injection (50
.mu.g/mouse), resulting in a fast onset of inflammation. Compound
treatment is continued until 10 days after the mAb injection.
Inflammation is read by measuring paw swelling and recording the
clinical score of each paw. The cumulative clinical arthritis score
of four limbs is presented to show the severity of inflammation. A
scoring system is applied to each limb using a scale of 0-4, with 4
being the most severe inflammation. [1290] 0 Symptom free [1291] 1
Mild, but definite redness and swelling of one type of joint such
as the ankle or wrist, or apparent redness and swelling limited to
individual digits, regardless of the number of affected digits
[1292] 2 Moderate redness and swelling of two or more types of
joints [1293] 3 Severe redness and swelling of the entire paw
including digits [1294] 4 Maximally inflamed limb with involvement
of multiple joints
5.6. Mouse IBD Model
[1295] The mouse chronic dextran sodium sulphate (DSS)-induced
inflammatory bowel disease (IBD) model is a well validated disease
model for inflammatory bowel disease (Sina et al. 2009; Wirtz and
Neurath 2007).
[1296] To induce a chronic colitis, female BALB/c mice are fed with
4% DSS dissolved in drinking water for 4 days, followed by 3 days
of regular drinking water. This cycle is repeated three times. This
protocol induces a strong colitis while avoiding high mortality
rates. Animals are divided into several groups: [1297] a. intact
(water; vehicle alone, n=10), [1298] b. diseased (DSS; vehicle
alone, n=10), [1299] c. sulfazalazine used as reference (DSS; 20
mg/kg/day sulfazalazine, p.o., n=10) and [1300] d. the tested
compound (DSS; 1, 3, 10 and 30 mg/kg/day test compound, p.o.,
n=10/dose).
[1301] Clinical parameters are measured daily. The disease activity
index (DAI) is a combination of the individual scores for weight
loss, stool consistency and rectal bleeding. At necropsy, the
complete colons are removed and rinsed with sterile PBS. Segments
of the distal colon are dissected for histological analysis, gene
expression and protein level measurement.
5.7. Mouse Asthma Model
[1302] In vitro and in vivo models to validate efficacy of small
molecules towards asthma are described by (Alba et al. 2010; Nials
and Uddin 2008; Park et al. 2013; Kudlacz et al. 2008).
5.8. LPS Induced Lung Inflammation Model
5.8.1. Overview
[1303] The aim of the assay is to assess the effect of a test
compound in a mouse model of acute lung inflammation induced by
intranasal instillation of LPS. The impact on the induced cells
recruitment in lung is evaluated by measurement of white cells
count in broncho-alveolar lavage (BAL) fluid with VetABC device
(medical solution gmbh, Rothusstrasse 23, 6331 Hunenberg,
Switzerland).
5.8.2. Protocol
[1304] The animals (BALB/cJ mice, 18-20 g) are obtained from Harlan
Laboratories (Maison-Alfort, France). The animals are maintained on
12 hours light/dark cycle at 22.degree. C. with ad libitum access
to tap water and food. Litters are changed twice a week. For each
tested compound, a group of 10 subjects is used. In addition to the
test compound-treated groups, a vehicle+LPS control group (inLPS),
a non treated group (intact), and a positive control dexamethasone
treated group (DEX) are used.
[1305] LPS is dissolved in saline solution in order to obtain a
final 10 .mu.g/50 .mu.L solution for intranasal instillation, and
administered at 50 .mu.L/mouse by intranasal instillation.
[1306] The test compounds are prepared in 15 mL PEG200 (9
mL)/H.sub.2O (6 mL) to be dosed in a range of 0.3, 1, 3, 10, and 30
mg/kg, and then kept at room temperature in the dark, and are
administered once (qd) or twice daily (bid) over 2 days.
[1307] Dexamethasone (10 mg/kg, bid, po) is used as a positive
control.
[1308] On day 1, mice are anaesthetized by isoflurane inhalation.
During breathing, LPS solution is instilled intra-nasally and mice
are monitored until complete recovery from anaesthesia.
[1309] On day 2, mice are anaesthetized by intra-peritoneal
injection (under a volume of 10 mL/kg) of anaesthetic solution (18
mL NaCl 0.9%+0.5 mL xylazine (5 mg/kg)+1.5 mL ketamine (75
mg/kg)).
[1310] The trachea is canulated with a catheter, and BAL is
performed by 2.times.0.75 mL sterile PBS. The BAL fluid removed is
shaked gently at room temperature before centrifugation at 1500
r.p.m. during 10 min at 4.degree. C.
[1311] The supernatant is removed and the cell pellet is suspended
in 200 .mu.L of PBS, kept on ice and total cell count is processed
with VetABC device. Finally, mice are sacrificed under
anaesthesia.
5.8.3. Data Analysis
[1312] For each readout, mean and sem are calculated. A difference
statistically significant between intact or treated groups and
inLPS Vehicle group is evaluated with Prism.RTM. software using a
one-way ANOVA (for treatment groups) followed by a Student test. *:
p<0.05; **: p<0.01; ***: p<0.001 versus inLPS Vehicle
group.
[1313] Illustrative compounds tested according to this protocol are
reported in the table below.
TABLE-US-00009 TABLE VIII in-LPS test results Dose Effect
significance on Cpd# (bid po mg/kg) recruited BALF cells 42 30 ***
3 *** 10 *** 10 ** 33 10 ** 34 10 * 44 3 ** 201 10 **
5.9. Pharmakokinetic Studies in Rodents and Dogs
5.9.1. Animals
[1314] Male Sprague-Dawley rats (180-200 g) and female C57BL/6Rj
mice (18-22 g) are obtained from Janvier (France). Non-naive male
Beagle dogs (8-13 kg) are obtained from Marshall BioResources
(Italy). Two days before administration of compound, rats undergo
surgery to place a catheter in the jugular vein under isoflurane
anesthesia. Before oral dosing, animals are deprived of food for at
least 16 h before dosing until 4 h after. Water is provided ad
libitum. All in vivo experiments are carried out in a dedicated
pathogen free facility (22.degree. C.).
5.9.2. Pharmacokinetic Study
[1315] Compounds are formulated in PEG200/water for injection
(25/75, v/v) for the intravenous route and in PEG200/0.5%
methylcellulose (25/75, v/v) for the oral route.
5.9.2.1. Rodents
[1316] Compounds are orally dosed as a single esophageal gavage at
5 mg/kg (dosing volume of 5 mL/kg) and intravenously dosed as a
bolus via the caudal vein at 1 mg/kg (dosing volume of 5 mL/kg). In
the rat studies, each group consists of three rats and blood
samples are collected via the jugular vein. In the mouse studies,
each group consists of 21 mice (n=3/time point) and blood samples
are collected by intra-cardiac puncture under isoflurane
anesthesia. Li-heparin is used as anti-coagulant and blood is taken
at 0.05, 0.25, 0.5, 1, 3, 5, 8 and 24 h (i.v. route) and 0.25, 0.5,
1, 3, 5, 8 and 24 h (p.o. route).
5.9.2.2. Dogs
[1317] Compounds are dosed to three animals i.v. via a 10 min
infusion in the cephalic vein with a dose level of 1 mg/kg (dose
volume of 2 mL/kg) and after a washout of minimally 3 days, dosed
orally as a single gavage with a dose level of 5 mg/kg (dose volume
of 2 mL/kg). Blood samples are taken from the jugular vein using
vacutainers and Li-heparin as anticoagulant at 0.083, 0.167, 0.5,
1, 2, 4, 6, 8, 10 and 24 h (i.v.) and at 0.25, 0.5, 1, 2, 3, 4, 6,
8, 10 and 24 h (p.o.).
5.9.3. Quantification of Compound Levels in Plasma
[1318] Whole blood samples are centrifuged at 5000 rpm for 10 min
and the resulting plasma samples are stored at -20.degree. C.
pending analysis. Plasma concentrations of each test compound are
determined by an LC-MS/MS method
5.9.4. Determination of Pharmacokinetic Parameters
[1319] Pharmacokinetic parameters are calculated using
Winnonlin.RTM. (Pharsight.RTM., United States).
5.9.5. 5-Day Rat Toxicity Study
[1320] A 5-day oral toxicity study with test compounds is performed
in Sprague-Dawley male rats to assess their toxic potential and
toxicokinetics, at daily doses of 100, 300 and 600 mg/kg/day, by
gavage, at the constant dosage-volume of 20 mL/kg/day.
[1321] The test compounds are formulated in PEG200/0.5%
methylcellulose (25/75, v/v). Each group included 6 principal male
rats as well as 3 satellite animals for toxicokinetics. A fourth
group is given PEG200/0.5% methylcellulose (25/75, v/v) only, at
the same frequency, dosage volume and by the same route of
administration, and acted as the vehicle control group.
[1322] The goal of the study is to determine the lowest dose that
resulted in no adverse events (no observable adverse effect
level--NOAEL).
5.9.6. Hepatocyte Stability
[1323] Models to evaluate metabolic clearance in hepatocyte are
described by (McGinnity et al. 2004).
5.9.7. Liability for QT Prolongation
[1324] Potential for QT prolongation is assessed in the hERG patch
clamp assay.
[1325] Whole-cell patch-clamp recordings are performed using an
EPC10 amplifier controlled by Pulse v8.77 software (HEKA). Series
resistance is typically less than 10 M.OMEGA. and compensated by
greater than 60%, recordings are not leak subtracted. Electrodes
are manufactured from GC150TF pipette glass (Harvard).
[1326] The external bathing solution contains: 135 mM NaCl, 5 mM
KCl, 1.8 mM CaCl.sub.2, 5 mM Glucose, 10 mM HEPES, pH 7.4.
[1327] The internal patch pipette solution contains: 100 mM
Kgluconate, 20 mM KCl, 1 mM CaCl.sub.2, 1 mM MgCl.sub.2, 5 mM
Na.sub.2ATP, 2 mM Glutathione, 11 mM EGTA, 10 mM HEPES, pH 7.2.
[1328] Drugs are perfused using a Biologic MEV-9/EVH-9 rapid
perfusion system.
[1329] All recordings are performed on HEK293 cells stably
expressing hERG channels. Cells are cultured on 12 mm round
coverslips (German glass, Bellco) anchored in the recording chamber
using two platinum rods (Goodfellow). hERG currents are evoked
using an activating pulse to +40 mV for 1000 ms followed by a tail
current pulse to -50 mV for 2000 ms, holding potential is -80 mV.
Pulses are applied every 20 s and all experiments are performed at
rt.
EXAMPLE 6
ADME
6.1. Kinetic Solubility
[1330] Starting from a 10 mM stock in DMSO, a serial dilution of
the compound is prepared in DMSO. The dilution series is
transferred to a 96 NUNC Maxisorb plate F-bottom (Cat no. 442404)
and 0.1M phosphate buffer pH 7.4 or 0.1M citrate buffer pH 3.0 at
room temperature is added.
[1331] The final concentration will range from 300 .mu.M to 18.75
.mu.M in 5 equal dilution steps. The final DMSO concentration does
not exceed 3%. 200 .mu.M Pyrene is added to the corner points of
each 96 well plate and serves as a reference point for calibration
of Z-axis on the microscope.
[1332] The assay plates are sealed and incubated for 1 h at
37.degree. C. while shaking at 230 rpm. The plates are then scanned
under a white light microscope, yielding individual pictures of the
precipitate per concentration. The precipitate is analyzed and
converted into a number with a software tool which can be plotted
onto a graph. The first concentration at which the compound appears
completely dissolved is the concentration reported; however the
true concentration lies somewhere between this concentration and
one dilution step higher.
[1333] Solubility values mesured according to this protocol are
reported in .mu.M and .mu.g/mL.
6.2. Plasma Protein Binding (Equilibrium Dialysis)
[1334] A 10 mM stock solution of the compound in DMSO is diluted
with a factor 5 in DMSO. This solution is further diluted in
freshly thawed human, rat, mouse or dog plasma (BioReclamation INC)
with a final concentration of 5 .mu.M and final DMSO concentration
of 0.5% (5.5 .mu.L in 1094.5 .mu.L plasma in a PP-Masterblock 96
well (Greiner, Cat no. 780285))
[1335] A Pierce Red Device plate with inserts (ThermoScientific,
Cat no. 89809) is prepared and filled with 750 .mu.L PBS in the
buffer chamber and 500 .mu.L of the spiked plasma in the plasma
chamber. The plate is incubated for 4 h at 37.degree. C. while
shaking at 230 rpm. After incubation, 120 .mu.L of both chambers is
transferred to 360 .mu.L acetonitrile in a 96-well round bottom, PP
deep-well plates (Nunc, Cat no. 278743) and sealed with an aluminum
foil lid. The samples are mixed and placed on ice for 30 min. This
plate is then centrifuged 30 min at 1200 rcf at 4.degree. C. and
the supernatant is transferred to a 96 v-bottom PP plate (Greiner,
651201) for analysis on LC-MS.
[1336] The plate is sealed with sealing mats (MA96RD-04S) of
Kinesis, Cambs, PE19 8YX, UK and samples are measured at room
temperature on LC-MS (ZQ 1525 from Waters) under optimized
conditions using Quanoptimize to determine the appropriate mass of
the molecule.
[1337] The samples are analyzed by LC-MS. Peak area from the
compound in the buffer chamber and the plasma chamber are
considered to be 100% compound. The percentage bound to plasma is
derived from these results and is repor.sub.ted as percentage bound
to plasma.
[1338] The solubility of the compound in the final test
concentration in PBS is inspected by microscope to indicate whether
precipitation is observed or not.
6.3. Microsomal Stability
[1339] A 10 mM stock solution of compound in DMSO is diluted to 6
.mu.M in a 105 mM phosphate buffer, pH 7.4 in a 96 deep well plate
(Greiner, Cat no. 780285) and pre-warmed at 37.degree. C.
[1340] A Glucose-6-phosphate-dehydrogenase (G6PDH, Roche,
10127671001) working stock solution of 700 U/mL is diluted with a
factor 1:700 in a 105 mM phosphate buffer, pH 7.4. A co-factor mix
containing 0.528M MgCl.sub.2.6H.sub.2O (Sigma, M2670), 0.528M
glucose-6-phosphate (Sigma, G-7879) and 0.208M NADP+ (Sigma,
N-0505) is diluted with a factor 1:8 in a 105 mM phosphate buffer,
pH 7.4.
[1341] A working solution is made containing 1 mg/mL liver
microsomes (Provider, Xenotech) of the species of interest (human,
mouse, rat, dog, . . . ), 0.8 U/mL G6PDH and co-factor mix (6.6 mM
MgCl.sub.2, 6.6 mM glucose-6-phosphate, 2.6 mM NADP+). This mix is
pre-incubated for 15 min, but never more than 20 min, at room
temperature.
[1342] After pre-incubation, compound dilution and the mix
containing the microsomes, are added together in equal amount and
incubated for 30 min at 300 rpm. For the time point of 0 min, two
volumes of methanol are added to the compound dilution before the
microsome mix is added. The final concentration during incubation
are: 3 .mu.M test compound or control compound, 0.5 mg/mL
microsomes, 0.4 U/mL G6PDH, 3.3 mM MgCl.sub.2, 3.3 mM
glucose-6-phosphate and 1.3 mM NaDP+.
[1343] After 30 min of incubation, the reaction is stopped with 2
volumes of methanol.
[1344] Of both time points, samples are mixed, centrifuged and the
supernatant is harvested for analysis on LC-MS/MS. The instrument
responses (i.e. peak heights) are referenced to the zero time-point
samples (as 100%) in order to determine the percentage of compound
remaining. Standard compounds Propanolol and Verapamil are included
in the assay design.
[1345] The data on microsomal stability are expressed as a
percentage of the total amount of compound remaining after 30
min.
6.4. CYP Inhibition
6.4.1. Direct CYP Inhibition
[1346] The in vitro direct inhibitory potential (IC50) of the
compounds on cytochrome P450 isoenzymes in pooled human liver
microsomes (HLM) is determined based on the draft FDA Guidance for
Industry (Drug Interaction Studies--Study Design, Data Analysis,
Implications for Dosing, and Labeling Recommendations), 2006,
http://www.fda.gov/cder/guidance/index.htm.
[1347] The following probe substrates are used: phenacetin for
CYP1A2, diclofenac for CYP2C9, S(+)-mephenytoin for CYP2C19,
bufuralol for CYP2D6 and testosterone for CYP3A4. The following
positive control inhibitors are used: .alpha.-naphtoflavone for
CYP1A2, sulfaphenazole for CYP2C9, tranylcypromine for CYP2C19,
quinidine for CYP2D6 and ketoconazole for CYP3A4.
6.4.2. Time-Dependent CYP3A4 Inhibition
[1348] Time-dependent CYP3A4 inhibition by the compounds, assessed
in pooled HLM, is determined via IC.sub.50 determination according
to Grimm et al. Drug Metabolism and Disposition 2009, 37, 1355-1370
and the draft FDA Guidance for Industry (Drug Interaction
Studies--Study Design, Data Analysis, Implications for Dosing, and
Labeling Recommendations), 2006,
http://www.fda.gov/cder/guidance/index.htm. Testosterone is used as
probe substrate and troleandomycin is used as positive control.
6.5. Caco2 Permeability
[1349] Bi-directional Caco-2 assays are performed as described
below. Caco-2 cells are obtained from European Collection of Cell
Cultures (ECACC, cat 86010202) and used after a 21 day cell culture
in 24-well Transwell plates (Fisher TKT-545-020B).
[1350] 2.times.105 cells/well are seeded in plating medium
consisting of DMEM+GlutaMAXI+1% NEAA+10% FBS (FetalClone II)+1%
Pen/Strep. The medium is changed every 2-3 days.
[1351] Test and reference compounds (propranolol and rhodamine123
or vinblastine, all purchased from Sigma) are prepared in Hanks'
Balanced Salt Solution containing 25 mM HEPES (pH 7.4) and added to
either the apical (125 .mu.L) or basolateral (600 .mu.L) chambers
of the Transwell plate assembly at a concentration of 10 .mu.M with
a final DMSO concentration of 0.25%.
[1352] 50 .mu.M Lucifer Yellow (Sigma) is added to the donor buffer
in all wells to assess integrity of the cell layers by monitoring
Lucifer Yellow permeation. As Lucifer Yellow (LY) cannot freely
permeate lipophilic barriers, a high degree of LY transport
indicates poor integrity of the cell layer.
[1353] After a 1 hr incubation at 37.degree. C. while shaking at an
orbital shaker at 150 rpm, 70 .mu.L aliquots are taken from both
apical (A) and basal (B) chambers and added to 100 .mu.L 50:50
acetonitrile:water solution containing analytical internal standard
(0.5 .mu.M carbamazepine) in a 96 well plate.
[1354] Lucifer yellow is measured with a Spectramax Gemini XS (Ex
426 nm and Em 538 nm) in a clean 96 well plate containing 150 .mu.L
of liquid from basolateral and apical side.
[1355] Concentrations of compound in the samples are measured by
high performance liquid-chromatography/mass spectroscopy
(LC-MS/MS).
[1356] Apparent permeability (Papp) values are calculated from the
relationship:
Papp=[compound]acceptor final.times.Vacceptor/([compound]donor
initial.times.Vdonor)/Tinc.times.Vdonor/surface
area.times.60.times.10.sup.-6 cm/s
[1357] V=chamber volume
[1358] Tinc=incubation time.
[1359] Surface area=0.33 cm.sup.2
[1360] The Efflux ratios, as an indication of active efflux from
the apical cell surface, are calculated using the ratio of Papp
B>A/Papp A>B.
[1361] The following assay acceptance criteria are used:
[1362] Propranolol: Papp (A>B) value .gtoreq.20(.times.10.sup.-6
cm/s)
[1363] Rhodamine 123 or Vinblastine: Papp (A>B) value <5
(.times.10.sup.-6 cm/s) with Efflux ratio .gtoreq.5.
[1364] Lucifer yellow permeability: .ltoreq.100 nm/s
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FINAL REMARKS
[1437] It will be appreciated by those skilled in the art that the
foregoing descriptions are exemplary and explanatory in nature, and
intended to illustrate the invention and its preferred embodiments.
Through routine experimentation, an artisan will recognize apparent
modifications and variations that may be made without departing
from the spirit of the invention. All such modifications coming
within the scope of the appended claims are intended to be included
therein. Thus, the invention is intended to be defined not by the
above description, but by the following claims and their
equivalents.
[1438] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication are
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[1439] It should be understood that factors such as the
differential cell penetration capacity of the various compounds can
contribute to discrepancies between the activity of the compounds
in the in vitro biochemical and cellular assays.
[1440] At least some of the chemical names of compound of the
invention as given and set forth in this application, may have been
generated on an automated basis by use of a commercially available
chemical naming software program, and have not been independently
verified. Representative programs performing this function include
the Lexichem naming tool sold by Open Eye Software, Inc. and the
Autonom Software tool sold by MDL, Inc. In the instance where the
indicated chemical name and the depicted structure differ, the
depicted structure will control.
* * * * *
References